Antibodies and chimeric antigen receptors specific for b-cell maturation antigen

ABSTRACT

Provided herein are BCMA-binding molecules, including anti-BCMA antibodies and antigen-binding fragments thereof such as heavy chain variable (VH) regions and single-chain antibody fragments, and chimeric receptors comprising the anti-BCMA binding molecules such as chimeric antigen receptors (CARs). In some embodiments, the anti-BCMA antibodies or antigen-binding fragments thereof specifically bind to BCMA-1. Among the anti-BCMA antibodies are human antibodies, including those that compete for binding to BCMA with reference antibodies, such as a non-human reference antibody. Also provided are genetically engineered cells expressing the CARs or BCMA-binding molecules and uses thereof such as in adoptive cell therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.16/760,411, filed Apr. 29, 2020, which is a national stage applicationunder 35 U.S.C. § 371 of International Application No.PCT/US2018/058767, filed internationally on Nov. 1, 2018, which claimspriority from U.S. provisional application No. 62/580,431, filed Nov. 1,2017, entitled “ANTIBODIES AND CHIMERIC ANTIGEN RECEPTORS SPECIFIC FORB-CELL MATURATION ANTIGEN,” and U.S. provisional application No.62/596,772, filed Dec. 8, 2017, entitled “ANTIBODIES AND CHIMERICANTIGEN RECEPTORS SPECIFIC FOR B-CELL MATURATION ANTIGEN,” the contentsof which are incorporated by reference in their entirety.

INCORPORATION BY REFERENCE OF SEQUENCE LISTING

The present application is being filed along with a Sequence Listing inelectronic format. The Sequence Listing is provided as a file entitled735042004310SeqList.xml, created Feb. 21, 2023, which is 1,045,482 bytesin size. The information in the electronic format of the SequenceListing is incorporated by reference in its entirety.

FIELD

The present disclosure relates in some aspects to BCMA-bindingmolecules, in particular, to anti-BCMA antibodies, including antibodyfragments. The present disclosure further relates to recombinantreceptors containing such antibodies, including chimeric antigenreceptors (CARs), which contain such antibodies. The disclosure furtherrelates to genetically engineered cells expressing such receptors andantibodies, and use thereof in adoptive cell therapy.

BACKGROUND

B-cell maturation antigen (BCMA) is a transmembrane type III proteinexpressed on mature B lymphocytes. Upon binding of BCMA to its ligands,B cell activator of the TNF family (BAFF) and a proliferation inducingligand (APRIL), a pro-survival cell signal is delivered to the B cellwhich has been found to be required for plasma cell survival. Theexpression of BCMA has been linked to several diseases including cancer,autoimmune disorders and infectious diseases. Due to the role of BCMA invarious diseases and conditions, including cancer, BCMA is a therapeutictarget. Various BCMA-binding molecules, including anti-BCMA antibodiesand chimeric antigen receptors containing anti-BCMA antibody portionsand cells expressing such chimeric antigen receptors, are available.Improved BCMA-binding molecules and engineered BCMA-targeting cells areneeded. For example, there is a need for molecules and cells withreduced immunogenicity and fully human antibodies, including antibodyfragments that specifically bind to BCMA, and chimeric receptorsexpressing such human antibodies for use in adoptive cell therapy.Provided herein are embodiments that meet such needs.

SUMMARY

Provided herein are BCMA-binding molecules, including polypeptides, suchas anti-BCMA antibodies, including antigen-binding antibody fragmentssuch as single domain antibodies (e.g. V_(H) region alone), single-chainantibody fragments including scFv fragments, and polypeptides containingsuch antibodies, including fusion proteins, receptors, e.g., recombinantreceptors, including chimeric receptors such as chimeric antigenreceptors (CARs) containing the antibody as an antigen-recognitioncomponent. In particular embodiments, the antibodies are humanantibodies, such as human single-chain antibody fragments includingscFvs.

Provided herein are antibodies or antigen-binding fragments thereof,including those that specifically bind to BCMA, such as human BCMA. Insome embodiments, the antibodies contain particular complementaritydetermining regions (CDRs), including heavy chain CDRs (i.e., CDR-H1,CDR-H2, and/or CDR-H3) and light chain CDRs (i.e., CDR-L1, CDR-L2,and/or CDR-L3), such as any described herein. In some embodiments, theantibody or antigen-binding fragment thereof includes a heavy chainvariable (V_(H)) region. In some embodiments, the antibody orantigen-binding fragment thereof includes a V_(H) region and a lightchain variable (V_(L)) region.

In some embodiments, provided herein are antibodies or antigen-bindingfragments thereof, wherein the antibody or antigen-binding fragmentcomprises a V_(H) region comprising a heavy chain complementaritydetermining region 3 (CDR-H3) comprising the amino acid sequenceselected from any one of SEQ ID NOs:7-11, 149-157, 279-287 and 376-378or a CDR-H3 contained within the V_(H) region amino acid sequenceselected from any one of SEQ ID NOs:110-115, 247-256, 518-531 and 533.

In some aspects, provided herein are antibodies or antigen-bindingfragments thereof, wherein the antibody or antigen-binding fragmentcomprises a V_(H) region comprising at least 90% sequence identity tothe V_(H) region amino acid sequence selected from any one of SEQ IDNOs:110-115, 247-256, 518-531 and 533, such as at least 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

In some of any such embodiments, the V_(H) region comprises a CDR-H3comprising the amino acid sequence X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃X₁₄(SEQ ID NO:355), wherein Xi is A, D, E, G, L, V or W; X₂ is A, D, G, L,P, Q or S; X₃ is A, D, G, L or Y; X₄ is D, G, P, R, S, V, Y or null; X₅is D, I, P, S, T, Y or null; X₆ is A, G, I, S, T, V, Y or null; X₇ is A,D, E, F, L, P, S, Y or null; X₈ is P, Q, T, Y or null; X₉ is D, G, R, Yor null; X₁₀ is A, F, Y or null; X₁₁ is D, F or null; X₁₂ is F or null;X₁₃ is D, T or Y; and X₁₄ is I, L, N, V or Y.

In some of any such embodiments, the V_(H) region includes a CDR-H3comprising the amino acid sequence selected from any one of SEQ IDNOs:7-11, 149-157, 279-287 and 376-378 or a CDR-H3 contained within theV_(H) region amino acid sequence selected from any one of SEQ IDNOs:110-115, 247-256, 518-531 and 533.

In some of any such embodiments, the V_(H) region comprises a heavychain complementarity determining region 1 (CDR-H1) comprising the aminoacid sequence X₁X₂X₃MX₄ (SEQ ID NO:353) Xi is D or S; X₂ is Y or S; X₃is A, G, W, or Y; and X₄ is H, Q, or S; and/or a heavy chaincomplementarity determining region 2 (CDR-H2) comprising the amino acidsequence of X₁IX₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁YX₁₂X₁₃X₁₄X₁₅X₁₆X₁₇ (SEQ IDNO:354), wherein Xi is F, G, H, V, W or Y; X₂ is N, R, S or V; X₃ is P,Q, S, V, W or Y; X₄ is K or null; X₅ is A or null; X₆ is D, G, N, S, orY; X₇ is G or S; X₈ is G or S; X₉ is E, G, N, T or S; X₁₀ is I, K, or T;X₁₁ is E, G, N or Y; X₁₂ is A or V; X₁₃ is A, D or Q; X₁₄ is K or S; X₁₅is F or V; X₁₆ is K or Q; and X₁₇ is E or G.

In some of any such embodiments, the V_(H) region comprises a CDR-H1comprising the amino acid sequence selected from any one of SEQ IDNOs:1-3 and 140-144; and/or a CDR-H2 comprising the amino acid sequenceselected from any one of SEQ ID NOs:4-6, 145-148 and 372-374.

In some of any such embodiments, the V_(H) region comprises a CDR-H1contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs:110-115, 247-256, 518-531 and 533; and/or a CDR-H2contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs:110-115, 247-256, 518-531 and 533.

In some embodiments, provided herein are antibodies or antigen-bindingfragments thereof that include a CDR-H1 comprising the amino acidsequence selected from any one of SEQ ID NOs:1-3 and 140-144 or a CDR-H1contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs:110-115, 247-256, 518-531 and 533; a CDR-H2 comprisingthe amino acid sequence selected from any one of SEQ ID NOs:4-6, 145-148and 372-374 or a CDR-H2 contained within the V_(H) region amino acidsequence selected from any one of SEQ ID NOs:110-115, 247-256, 518-531and 533; and/or a CDR-H3 comprising the amino acid sequence selectedfrom any one of SEQ ID NOs:7-11, 149-157, 279-287 and 376-378 or aCDR-H3 contained within the V_(H) region amino acid sequence selectedfrom any one of SEQ ID NOs:110-115, 247-256, 518-531 and 533.

In some of any such embodiments, the antibody or antigen-bindingfragment thereof includes a V_(H) region comprising a CDR-H1, CDR-H2,and CDR-H3 selected from a CDR-H1, CDR-H2, and CDR-H3 comprising theamino acid sequence of SEQ ID NOs:1, 4, and 7, respectively; a CDR-H1,CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:2,5, and 8, respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising theamino acid sequence of SEQ ID NOs:2, 5, and 9, respectively; a CDR-H1,CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:2,5, and 10, respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising theamino acid sequence of SEQ ID NOs:3, 6, and 11, respectively; a CDR-H1,CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:140,145, and 149, respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising theamino acid sequence of SEQ ID NOs:141, 145, and 149, respectively; aCDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ IDNOs:141, 145, and 150, respectively; a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOs:142, 146, and 151,respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOs:2, 5, and 152, respectively; a CDR-H1, CDR-H2,and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:143, 147,and 153, respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising the aminoacid sequence of SEQ ID NOs:144, 148, and 154, respectively; a CDR-H1,CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:3,6, and 155, respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising theamino acid sequence of SEQ ID NOs:2, 5, and 156, respectively; a CDR-H1,CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:2,5, and 157, respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising theamino acid sequence of SEQ ID NOs:2, 6, and 376, respectively; a CDR-H1,CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:3,372, and 376, respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising theamino acid sequence of SEQ ID NOs:3, 6, and 376, respectively; a CDR-H1,CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:3,6, and 377, respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising theamino acid sequence of SEQ ID NOs:2, 373, and 152, respectively; aCDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ IDNOs:2, 5, and 378, respectively; or a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOs:2, 374, and 9,respectively.

In some embodiments, provided herein are antibodies or antigen-bindingfragments thereof comprising a V_(H) region comprising a CDR-H1, aCDR-H2, and a CDR-H3, respectively, comprising the amino acid sequenceof a CDR-H1, a CDR-H2, and a CDR-H3 contained within the V_(H) regionamino acid sequence selected from any one of SEQ ID NOs:110-115,247-256, 518-531 and 533.

In some of any such embodiments, the V_(H) region comprises a frameworkregion 1 (FR1), a FR2, a FR3, and/or a FR4 comprising at least 90%sequence identity, respectively, to a FR1, FR2, FR3, and/or FR4contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs:110-115, 247-256, 518-531 and 533. In someembodiments, the V_(H) region contains a framework region 1 (FR1), aFR2, a FR3, and/or a FR4 sequence comprising at least 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity, respectively, toa FR1, FR2, FR3, and/or FR4 contained within the V_(H) region amino acidsequence selected from any one of SEQ ID NOs:110-115, 247-256, 518-531and 533. In some embodiments, the V_(H) region comprises a FR1, a FR2, aFR3, and/or a FR4, selected from: a FR1 comprising the amino acidsequence selected from any one of SEQ ID NOs:59-63, 195-203 and 434-439;a FR2 comprising the amino acid sequence selected from any one of SEQ IDNOs:64-66 and 204-209; a FR3 comprising the amino acid sequence selectedfrom any one of SEQ ID NOs:67-69, 210-216, 441 and 443; and/or a FR4comprising the amino acid sequence selected from any one of SEQ IDNOs:70-71, 217-220, 444 and 445.

In some of any such embodiments, the V_(H) region comprises the aminoacid sequence selected from any one of SEQ ID NOs:110-115, 247-256,518-531 and 533.

In some of any such embodiments, the antibody or antigen-bindingfragment does not comprise a light chain variable (V_(L)) region, doesnot comprise a light chain complementarity determining region (CDR-L1),CDR-L2, and/or CDR-L3, and/or is a single-domain antibody (sdAb)comprising only the V_(H) region. In some embodiments, the antibody orantigen-binding fragment is an sdAb comprising only the V_(H) region.

In some embodiments of any of the antibodies or fragments containing anyof the above V_(H) region sequences, the antibody or fragment furthercontains a V_(L) region. In some such embodiments, the V_(L) regioncomprises at least 90% sequence identity to the V_(L) region amino acidsequence selected from any one of SEQ ID NOs:116-127, 257-267, 534-550and 552-557, such as at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99% sequence identity to the V_(L) region amino acid sequenceselected from any one of SEQ ID NOs:116-127, 257-267, 534-550 and552-557.

In some of any such embodiments, the V_(L) region comprises a lightchain complementarity determining region 3 (CDR-L3) comprising the aminoacid sequence X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂, (SEQ ID NO:358), wherein Xiis A, C, G, H, I, Q or S; X₂ is A, Q, S or V; X₃ is 5, W or Y; X₄ is D,F, G, H or Y; X₅ is D, G, M, R, S or T; X₆ is A, G, H, L, R, S, T or Y;X₇ is L, P, R, S or null; X₈ is D, G, N, R, S, T or null; X₉ is A, G, H,L, P or null; X₁₀ is F, S or null; X₁₁ is L, P, W or Y; and X₁₂ is S, Tor V.

In some of any such embodiments, the V_(L) region comprises a CDR-L3comprising the amino acid sequence selected from any one of SEQ IDNOs:47-58, 184-194, 415-427 and 429-433, or a CDR-L3 contained withinthe V_(L) region amino acid sequence selected from any one of SEQ IDNOs:116-127, 257-267, 534-550 and 552-557.

In some of any such embodiments, the V_(L) region comprises a lightchain complementarity determining region 1 (CDR-L1) comprising the aminoacid sequence of X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃X₁₄X₁₅X₁₆X₁₇ (SEQ IDNO:356), wherein Xi is G, K, R, S or T; X₂ is A, G or S; X₃ is G, N, Sor T; X₄ is G, K, N, Q, R or S; X₅ is S or null; X₆ is D, N, V or null;X₇ is L, V or null; X₈ is H, S, Y or null; X₉ is S, T or null; X₁₀ is Sor null; X₁₁ is D, G, I, N, S or null; X₁₂ is D, E, G, K, I, N or null;X₁₃ is F, G, K, N, R, S, Y or null; X₁₄ is D, K, N, T or null; X₁₅ is A,D, G, L, N, S, T or Y; X₁₆ is L or V; X₁₇ is A, H, N, Q or S; and/or alight chain complementarity determining region 2 (CDR-L2) comprising theamino acid sequence of X₁X₂X₃X₄X₅X₆X₇ (SEQ ID NO:357), wherein Xi is A,D, E, N, S, V or W; X₂ is A, D, N, S or V; X₃ is A, D, H, I, N or S; X₄is D, K, N, Q, R or T; X₅ is L, R or V; X₆ is A, E, P or Q; and X₇ is A,D, S or T.

In some of any such embodiments, the V_(L) region comprises a CDR-L1comprising the amino acid sequence selected from any one of SEQ IDNOs:26-36, 174-178, 380-392 and 394-398; and/or a CDR-L2 comprising theamino acid sequence selected from any one of SEQ ID NOs:37-46, 179-183,399-409 and 411-414.

In some of any such embodiments, the V_(L) region comprises a CDR-L1contained within the V_(L) region amino acid sequence selected from anyone of SEQ ID NOs:116-127, 257-267, 534-550 and 552-557; and/or a CDR-L2contained within the V_(L) region amino acid sequence selected from anyone of SEQ ID NOs:116-127, 257-267, 534-550 and 552-557.

In some of any such embodiments, the V_(L) region comprises a CDR-L1comprising the amino acid sequence selected from any one of SEQ IDNOs:26-36, 174-178, 380-392 and 394-398; a CDR-L2 comprising the aminoacid sequence selected from any one of SEQ ID NOs:37-46, 179-183,399-409 and 411-414; and a CDR-L3 comprising the amino acid sequenceselected from any one of SEQ ID NOs:47-58, 184-194, 415-427 and 429-433.

In some of any such embodiments, the antibody or antigen-bindingfragment thereof includes a V_(L) region comprising a CDR-L1, CDR-L2,and CDR-L3 selected from: a CDR-L1, CDR-L2, and CDR-L3 comprising theamino acid sequence of SEQ ID NOs:26, 37, and 47, respectively; aCDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ IDNOs:27, 38, and 48, respectively; a CDR-L1, CDR-L2, and CDR-L3comprising the amino acid sequence of SEQ ID NOs:28, 39, and 49,respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:29, 40, and 50, respectively; a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:30, 39, and51, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:31, 41, and 52, respectively; a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:32, 42, and53, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:30, 39, and 54, respectively; a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:33, 43, and55, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:34, 44, and 56, respectively; a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:35, 45, and57, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:36, 46, and 58, respectively; a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:174, 179,and 184, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the aminoacid sequence of SEQ ID NOs:174, 179, and 185, respectively; a CDR-L1,CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:174,179, and 186, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising theamino acid sequence of SEQ ID NOs:174, 179, and 187, respectively; aCDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ IDNOs:175, 180, and 188, respectively; a CDR-L1, CDR-L2, and CDR-L3comprising the amino acid sequence of SEQ ID NOs:174, 179, and 189,respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:176, 181, and 190, respectively; a CDR-L1,CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:177,182, and 191, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising theamino acid sequence of SEQ ID NOs:174, 179, and 192, respectively; aCDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ IDNOs:178, 183, and 193, respectively; a CDR-L1, CDR-L2, and CDR-L3comprising the amino acid sequence of SEQ ID NOs:178, 183, and 194,respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:30, 399, and 415, respectively; a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:380, 400,and 416, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the aminoacid sequence of SEQ ID NOs:33, 43, and 421, respectively; a CDR-L1,CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:381,401, and 417, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising theamino acid sequence of SEQ ID NOs:382, 402, and 418, respectively; aCDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ IDNOs:383, 403, and 419, respectively; a CDR-L1, CDR-L2, and CDR-L3comprising the amino acid sequence of SEQ ID NOs:384, 39, and 54,respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:385, 180, and 58, respectively; a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:175, 180,and 188, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the aminoacid sequence of SEQ ID NOs:386, 404, and 420, respectively; a CDR-L1,CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:387,405, and 422, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising theamino acid sequence of SEQ ID NOs:388, 406, and 423, respectively; aCDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ IDNOs:388, 407, and 424, respectively; a CDR-L1, CDR-L2, and CDR-L3comprising the amino acid sequence of SEQ ID NOs:389, 408, and 425,respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:390, 183, and 193, respectively; a CDR-L1,CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:391,409, and 426, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising theamino acid sequence of SEQ ID NOs:392, 40, and 427, respectively; aCDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ IDNOs:394, 39, and 429, respectively; a CDR-L1, CDR-L2, and CDR-L3comprising the amino acid sequence of SEQ ID NOs:395, 411, and 430,respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:396, 412, and 431, respectively; a CDR-L1,CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:396,412, and 58, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising theamino acid sequence of SEQ ID NOs:397, 413, and 432, respectively; or aCDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ IDNOs:398, 414, and 433, respectively.

In some of any such embodiments, the V_(L) region comprises the CDR-L1,CDR-L2, and CDR-L3, respectively, contained within the V_(L) regionamino acid sequence selected from any one of SEQ ID NOs:116-127,257-267, 534-550 and 552-557.

In some of any such embodiments, the V_(L) region comprises a frameworkregion 1 (FR1), a FR2, a FR3, and/or a FR4 comprising at least 90%sequence identity, respectively, to a FR1, FR2, FR3, and/or FR4 of theamino acid sequence contained within the V_(L) region amino acidsequence selected from any one of SEQ ID NOs:116-127, 257-267, 534-550and 552-557. In some embodiments, the V_(L) region comprises a frameworkregion 1 (FR1), a FR2, a FR3, and/or a FR4 sequence having at least 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98%, 99% sequence identity,respectively, to a FR1, FR2, FR3, and/or FR4 of the amino acid sequencecontained within the V_(L) region amino acid sequence selected from anyone of SEQ ID NOs:116-127, 257-267, 534-550 and 552-557. In someembodiments, the V_(H) region comprises a FR1, a FR2, a FR3, and/or aFR4, selected from a FR1 comprising the amino acid sequence selectedfrom any one of SEQ ID NOs:72-82, 221-227, 446-459 and 461-466; a FR2comprising the amino acid sequence selected from any one of SEQ IDNOs:83-92, 228-232, 467-477 and 479-482; a FR3 comprising the amino acidsequence selected from any one of SEQ ID NOs:93-101, 233-242, 483-495and 497-501; and/or a FR4 comprising the amino acid sequence selectedfrom any one of SEQ ID NOs:102-109, 243-246,502-506 and 508.

In some of any such embodiments, the V_(L) region comprises the aminoacid sequence selected from any one of SEQ ID NOs:116-127, 257-267,534-550 and 552-557.

Provided herein are antibodies or antigen-binding fragments thereofcomprising a CDR-H1, a CDR-H2, and a CDR-H3, respectively, comprisingthe amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 sequencescontained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs:110-115, 247-256, 518-531 and 533; and/or a CDR-L1,aCDR-L2, and aCDR-L3, respectively, comprising the amino acid sequencesof CDR-L1, CDR-L2, and CDR-L3 sequences contained within the V_(L)region amino acid sequence selected from any one of SEQ ID NOs:116-127,257-267, 534-550 and 552-557.

Provided herein are antibodies or antigen-binding fragments thereof,wherein said antibody or antigen-binding fragment comprises a heavychain variable (V_(H)) region having at least 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98% or 99% sequence identity to the V_(H) region aminoacid sequence selected from any one of SEQ ID NOs:110-115, 247-256,518-531 and 533; and a light chain variable (V_(L)) region having atleast 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequenceidentity to the V_(L) region amino acid sequence selected from any oneof SEQ ID NOs:116-127, 257-267, 534-550 and 552-557.

In some of any embodiments, said antibody or antigen-binding fragmentcomprises a V_(H) region having at least 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98% or 99% sequence identity to the V_(H) region amino acidsequence selected from any one of SEQ ID NOs:110, 256 and 519; and aV_(L) region having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity to the V_(L) region amino acid sequenceselected from any one of SEQ ID NOs:47, 51, 194 and 416. In some of anyembodiments, said antibody or antigen-binding fragment comprises a V_(H)region having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or99% sequence identity to the V_(H) region amino acid sequence of SEQ IDNO:115; and a V_(L) region having at least 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity to the V_(L) region amino acidsequence of SEQ ID NO:536.

Provided herein are antibodies or antigen-binding fragments thereof,comprising: a heavy chain variable (V_(H)) region comprising a heavychain complementarity determining region 1 (CDR-H1), CDR-H2, and CDR-H3,wherein: the CDR-H1 comprises the amino acid sequence selected from anyone of SEQ ID NOs:1-3 and 140-144; the CDR-H2 comprises the amino acidsequence selected from any one of SEQ ID NOs:4-6, 145-148 and 372-374;and the CDR-H3 comprises the amino acid sequence selected from any oneof SEQ ID NOs:7-11, 149-157, 279-287 and 376-378; and a light chainvariable (V_(L)) region comprising a heavy chain complementaritydetermining region 1 (CDR-L1), CDR-L2, and CDR-L3, wherein: the CDR-L1comprises the amino acid sequence selected from any one of SEQ ID NOs:26-36, 174-178, 380-392 and 394-398; the CDR-L2 comprises the amino acidsequence selected from any one of SEQ ID NOs: 37-46, 179-183, 399-409and 411-414; and the CDR-L3 comprises the amino acid sequence selectedfrom any one of SEQ ID NOs:47-58, 184-194, 415-427 and 429-433.

In some of any embodiments, the CDR-H1 comprises the amino acid sequenceselected from any one of SEQ ID NOs:1 and 2; the CDR-H2 comprises theamino acid sequence selected from any one of SEQ ID NOs:4 and 5; and theCDR-H3 comprises the amino acid sequence selected from any one of SEQ IDNOs: 7 and 157; and the CDR-L1 comprises the amino acid sequenceselected from any one of SEQ ID NOs: 26, 30, 178 and 380; the CDR-L2comprises the amino acid sequence selected from any one of SEQ ID NOs:37, 39, 183 or 400; and the CDR-L3 comprises the amino acid sequenceselected from any one of SEQ ID NOs: 47, 51, 194 and 416. In some of anyembodiments, the CDR-H1 comprises the amino acid sequence of SEQ IDNO:2; the CDR-H2 comprises the amino acid sequence of SEQ ID NO:5; andthe CDR-H3 comprises the amino acid sequence of SEQ ID NO:10; and theCDR-L1 comprises the amino acid sequence of SEQ ID NO:33; the CDR-L2comprises the amino acid sequence of SEQ ID NO:43; and the CDR-L3comprises the amino acid sequence of SEQ ID NO:421.

Provided herein are antibodies or antigen-binding fragments thereof,comprising a heavy chain variable (V_(H)) region and a light chainvariable (V_(L)) region, wherein: the V_(H) region comprises a CDR-H1,CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:1,4, and 7, respectively, and the V_(L) region comprises a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence of SEQ ID NOS:26, 37, and47, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:2, 5, and 8,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:27, 38, and 48,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:28, 39, and 49,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:29, 40, and 50,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:30, 39, and 51,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:31, 41, and 52,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:32, 42, and 53,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:30, 39, and 54,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:2, 5, and 9,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:33, 43, and 55,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:2, 5, and 10,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:34, 44, and 56,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:3, 6, and 11,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:35, 45, and 57,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:2, 5, and 10,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:36, 46, and 58,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:140, 145, and 149,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:174, 179, and184, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:141, 145, and149, respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:174, 179, and185, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:141, 145, and150, respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:174, 179, and186, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:142, 146, and151, respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:174, 179, and187, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:2, 5, and 152,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:175, 180, and188, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:143, 147, and153, respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:174, 179, and189, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:144, 148, and154, respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:176, 181, and190, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:3, 6, and 155,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:177, 182, and191, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:2, 5, and 156,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:174, 179, and192, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:2, 5, and 157,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:178, 183, and193, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:2, 5, and 157,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:178, 183, and194, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:2, 6, and 376,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:30, 399, and415, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:380, 400, and416, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:2, 5, and 10,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:33, 43, and 421,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:3, 6, and 155,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:177, 182, and191, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:3, 372, and 376,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:381, 401, and417, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:3, 6, and 376,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:382, 402, and418, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:3, 6, and 377,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:383, 403, and419, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:384, 39, and 54,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:2, 5, and 10,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:385, 180, and58, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:2, 373, and 152,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:175, 180, and188, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:3, 6, and 11,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:386, 404, and420, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:2, 5, and 378,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:33, 43, and 421,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:2, 5, and 9,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:387, 405, and422, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:2, 5, and 9,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:388, 406, and423, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:2, 5, and 9,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:388, 407, and424, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:3, 6, and 376,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:389, 408, and425, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:2, 5, and 157,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:390, 183, and193, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:2, 374, and 9,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:391, 409, and426, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:392, 40, and427, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:394, 39, and429, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:395, 411, and430, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:28, 39, and 49,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:2, 5, and 10,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:396, 412, and431, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:2, 5, and 10,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:396, 412, and58, respectively; the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:2, 5, and 10,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:397, 413, and432, respectively; or the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:398, 414, and433, respectively.

In some of any embodiments, the V_(H) region comprises a CDR-H1, CDR-H2,and CDR-H3 comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:26, 37, and 47,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:30, 39, and 51,respectively; the V_(H) region comprises a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOS:2, 5, and 157,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:178, 183, and194, respectively; or the V_(H) region comprises a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOS:1, 4, and 7,respectively, and the V_(L) region comprises a CDR-L1, CDR-L2, andCDR-L3 comprising the amino acid sequence of SEQ ID NOS:380, 400, and416, respectively. In some of any embodiments, the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 10, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:33, 43, and 421, respectively.

Provided herein are antibodies or antigen-binding fragments thereof,comprising: a heavy chain complementarity determining region 1 (CDR-H1),CDR-H2, and CDR-H3, respectively, comprising the amino acid sequences ofCDR-H1, CDR-H2, and CDR-H3 contained within the V_(H) region amino acidsequence selected from any one of SEQ ID NOs:110-115, 247-256, 518-531and 533; and/or a light chain complementarity determining region 1(CDR-L1), CDR-L2, and CDR-L3, respectively, comprising the amino acidsequences of CDR-L1, CDR-L2, and CDR-L3 contained within the V_(L)region amino acid sequence selected from any one of SEQ ID NOs:116-127,257-267, 534-550 and 552-557.

In some of any embodiments, the CDR-H1, CDR-H2, and CDR-H3,respectively, comprise the amino acid sequences of CDR-H1, CDR-H2, andCDR-H3 contained within the V_(H) region amino acid sequence selectedfrom any one of SEQ ID NOs: 110, 256 and 519; and a light chaincomplementarity determining region 1 (CDR-L1), CDR-L2, and CDR-L3,respectively, comprising the amino acid sequences of CDR-L1, CDR-L2, andCDR-L3 contained within the V_(L) region amino acid sequence selectedfrom any one of SEQ ID NOs: 116, 120, 267 and 535.

In some of any embodiments, the CDR-H1, CDR-H2, and CDR-H3,respectively, comprise the amino acid sequences of CDR-H1, CDR-H2, andCDR-H3 contained within the V_(H) region amino acid sequence of SEQ IDNO:115; and a light chain complementarity determining region 1 (CDR-L1),CDR-L2, and CDR-L3, respectively, comprising the amino acid sequences ofCDR-L1, CDR-L2, and CDR-L3 contained within the V_(L) region amino acidsequence of SEQ ID NO:536.

Provided herein are antibodies or antigen-binding fragments thereof,comprising a heavy chain variable (V_(H)) region and a light chainvariable (V_(L)) region, wherein: the V_(H) region is or comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:110, and the V_(L) region is or comprises aCDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) region amino acidsequence of SEQ ID NO:116; the V_(H) region is or comprises a CDR-H1,CDR-H2 and CDR-H3 contained within the V_(H) region amino acid sequenceof SEQ ID NO:111, and the V_(L) region is or comprises a CDR-L1, CDR-L2and CDR-L3 contained within the V_(L) region amino acid sequence of SEQID NO:117; the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:110,and the V_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3contained within the V_(L) region amino acid sequence of SEQ ID NO:118;the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3 containedwithin the V_(H) region amino acid sequence of SEQ ID NO:110, and theV_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:119; the V_(H)region is or comprises a CDR-H1, CDR-H2 and CDR-H3 contained within theV_(H) region amino acid sequence of SEQ ID NO:110, and the V_(L) regionis or comprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L)region amino acid sequence of SEQ ID NO:120; the V_(H) region is orcomprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) regionamino acid sequence of SEQ ID NO:110, and the V_(L) region is orcomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:121; the V_(H) region is or comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:110, and the V_(L) region is or comprises aCDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) region amino acidsequence of SEQ ID NO:122; the V_(H) region is or comprises a CDR-H1,CDR-H2 and CDR-H3 contained within the V_(H) region amino acid sequenceof SEQ ID NO:110, and the V_(L) region is or comprises a CDR-L1, CDR-L2and CDR-L3 contained within the V_(L) region amino acid sequence of SEQID NO:123; the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:112,and the V_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3contained within the V_(L) region amino acid sequence of SEQ ID NO:124;the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3 containedwithin the V_(H) region amino acid sequence of SEQ ID NO:113, and theV_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:125; the V_(H)region is or comprises a CDR-H1, CDR-H2 and CDR-H3 contained within theV_(H) region amino acid sequence of SEQ ID NO:114, and the V_(L) regionis or comprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L)region amino acid sequence of SEQ ID NO:126; the V_(H) region is orcomprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) regionamino acid sequence of SEQ ID NO:115, and the V_(L) region is orcomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:127; the V_(H) region is or comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:247, and the V_(L) region is or comprises aCDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) region amino acidsequence of SEQ ID NO:257; the V_(H) region is or comprises a CDR-H1,CDR-H2 and CDR-H3 contained within the V_(H) region amino acid sequenceof SEQ ID NO:248, and the V_(L) region is or comprises a CDR-L1, CDR-L2and CDR-L3 contained within the V_(L) region amino acid sequence of SEQID NO:258; the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:249,and the V_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3contained within the V_(L) region amino acid sequence of SEQ ID NO:259;the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3 containedwithin the V_(H) region amino acid sequence of SEQ ID NO:250, and theV_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:260; the V_(H)region is or comprises a CDR-H1, CDR-H2 and CDR-H3 contained within theV_(H) region amino acid sequence of SEQ ID NO:251, and the V_(L) regionis or comprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L)region amino acid sequence of SEQ ID NO:261; the V_(H) region is orcomprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) regionamino acid sequence of SEQ ID NO:252, and the V_(L) region is orcomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:262; the V_(H) region is or comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:253, and the V_(L) region is or comprises aCDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) region amino acidsequence of SEQ ID NO:263; the V_(H) region is or comprises a CDR-H1,CDR-H2 and CDR-H3 contained within the V_(H) region amino acid sequenceof SEQ ID NO:254, and the V_(L) region is or comprises a CDR-L1, CDR-L2and CDR-L3 contained within the V_(L) region amino acid sequence of SEQID NO:264; the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:255,and the V_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3contained within the V_(L) region amino acid sequence of SEQ ID NO:265;the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3 containedwithin the V_(H) region amino acid sequence of SEQ ID NO:256, and theV_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:266; the V_(H)region is or comprises a CDR-H1, CDR-H2 and CDR-H3 contained within theV_(H) region amino acid sequence of SEQ ID NO:256, and the V_(L) regionis or comprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L)region amino acid sequence of SEQ ID NO:267; the V_(H) region is orcomprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) regionamino acid sequence of SEQ ID NO:518, and the V_(L) region is orcomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:534; the V_(H) region is or comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:519, and the V_(L) region is or comprises aCDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) region amino acidsequence of SEQ ID NO:535; the V_(H) region is or comprises a CDR-H1,CDR-H2 and CDR-H3 contained within the V_(H) region amino acid sequenceof SEQ ID NO:115, and the V_(L) region is or comprises a CDR-L1, CDR-L2and CDR-L3 contained within the V_(L) region amino acid sequence of SEQID NO:536; the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:520,and the V_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3contained within the V_(L) region amino acid sequence of SEQ ID NO:264;the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3 containedwithin the V_(H) region amino acid sequence of SEQ ID NO:521, and theV_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:537; the V_(H)region is or comprises a CDR-H1, CDR-H2 and CDR-H3 contained within theV_(H) region amino acid sequence of SEQ ID NO:522, and the V_(L) regionis or comprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L)region amino acid sequence of SEQ ID NO:538; the V_(H) region is orcomprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) regionamino acid sequence of SEQ ID NO:523, and the V_(L) region is orcomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:539; the V_(H) region is or comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:519, and the V_(L) region is or comprises aCDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) region amino acidsequence of SEQ ID NO:540; the V_(H) region is or comprises a CDR-H1,CDR-H2 and CDR-H3 contained within the V_(H) region amino acid sequenceof SEQ ID NO:524, and the V_(L) region is or comprises a CDR-L1, CDR-L2and CDR-L3 contained within the V_(L) region amino acid sequence of SEQID NO:541; the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:525,and the V_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3contained within the V_(L) region amino acid sequence of SEQ ID NO:261;the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3 containedwithin the V_(H) region amino acid sequence of SEQ ID NO:526, and theV_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:542; the V_(H)region is or comprises a CDR-H1, CDR-H2 and CDR-H3 contained within theV_(H) region amino acid sequence of SEQ ID NO:527, and the V_(L) regionis or comprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L)region amino acid sequence of SEQ ID NO:543; the V_(H) region is orcomprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) regionamino acid sequence of SEQ ID NO:528, and the V_(L) region is orcomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:544; the V_(H) region is or comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:529, and the V_(L) region is or comprises aCDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) region amino acidsequence of SEQ ID NO:545; the V_(H) region is or comprises a CDR-H1,CDR-H2 and CDR-H3 contained within the V_(H) region amino acid sequenceof SEQ ID NO:528, and the V_(L) region is or comprises a CDR-L1, CDR-L2and CDR-L3 contained within the V_(L) region amino acid sequence of SEQID NO:546; the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:522,and the V_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3contained within the V_(L) region amino acid sequence of SEQ ID NO:547;the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3 containedwithin the V_(H) region amino acid sequence of SEQ ID NO:256, and theV_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:548; the V_(H)region is or comprises a CDR-H1, CDR-H2 and CDR-H3 contained within theV_(H) region amino acid sequence of SEQ ID NO:530, and the V_(L) regionis or comprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L)region amino acid sequence of SEQ ID NO:549; the V_(H) region is orcomprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) regionamino acid sequence of SEQ ID NO:531, and the V_(L) region is orcomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:550; the V_(H) region is or comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:519, and the V_(L) region is or comprises aCDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) region amino acidsequence of SEQ ID NO:552; the V_(H) region is or comprises a CDR-H1,CDR-H2 and CDR-H3 contained within the V_(H) region amino acid sequenceof SEQ ID NO:110, and the V_(L) region is or comprises a CDR-L1, CDR-L2and CDR-L3 contained within the V_(L) region amino acid sequence of SEQID NO:553; the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:110,and the V_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3contained within the V_(L) region amino acid sequence of SEQ ID NO:118;the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3 containedwithin the V_(H) region amino acid sequence of SEQ ID NO:533, and theV_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:554; the V_(H)region is or comprises a CDR-H1, CDR-H2 and CDR-H3 contained within theV_(H) region amino acid sequence of SEQ ID NO:115, and the V_(L) regionis or comprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L)region amino acid sequence of SEQ ID NO:555; the V_(H) region is orcomprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) regionamino acid sequence of SEQ ID NO:524, and the V_(L) region is orcomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:556; or the V_(H) region is orcomprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) regionamino acid sequence of SEQ ID NO:519, and the V_(L) region is orcomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:557, respectively.

In some of any embodiments, the V_(H) region is or comprises a CDR-H1,CDR-H2 and CDR-H3 contained within the V_(H) region amino acid sequenceof SEQ ID NO:110, and the V_(L) region is or comprises a CDR-L1, CDR-L2and CDR-L3 contained within the V_(L) region amino acid sequence of SEQID NO:116; the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:110,and the V_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3contained within the V_(L) region amino acid sequence of SEQ ID NO:120;the V_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3 containedwithin the V_(H) region amino acid sequence of SEQ ID NO:256, and theV_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:267; or theV_(H) region is or comprises a CDR-H1, CDR-H2 and CDR-H3 containedwithin the V_(H) region amino acid sequence of SEQ ID NO:519, and theV_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:535. In some ofany embodiments, the V_(H) region is or comprises a CDR-H1, CDR-H2 andCDR-H3 contained within the V_(H) region amino acid sequence of SEQ IDNO:115, and the V_(L) region is or comprises a CDR-L1, CDR-L2 and CDR-L3contained within the V_(L) region amino acid sequence of SEQ ID NO:536,respectively.

Provided herein are antibodies or antigen-binding fragments thereofcomprising a V_(H) region and a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:110 and 116, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:111 and 117, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:110 and 118, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:110 and 119, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:110 and 120, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:110 and 121, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:110 and 122, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:110 and 123, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:112 and 124, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:113 and 125, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:114 and 126, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:115 and 127, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:247 and 257, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:248 and 258, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:249 and 259, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:250 and 260, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:251 and 261, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:252 and 262, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:253 and 263, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:254 and 264, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:255 and 265, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:256 and 266, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:256 and 267, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:518 and 534, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:519 and 535, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:115 and 536, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:520 and 264, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:521 and 537, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:522 and 538, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:523 and 539, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:519 and 540, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:524 and 541, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:525 and 261, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:526 and 542, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:527 and 543, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:528 and 544, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:529 and 545, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:528 and 546, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:522 and 547, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:256 and 548, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:530 and 549, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:531 and 550, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:519 and 552, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:110 and 553, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:110 and 118, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:533 and 554, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:115 and 555, respectively; a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:524 and 556, respectively; or a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:519 and 557, respectively.

In some of any embodiments, the antibody or antigen-binding fragmentcomprises a V_(H) region and a V_(L) regions comprising the amino acidsequence having at least 90% identity to SEQ ID NOs:110 and 116,respectively; a V_(H) region and a V_(L) regions comprising the aminoacid sequence having at least 90% identity to SEQ ID NOs:110 and 120,respectively; a V_(H) region and a V_(L) regions comprising the aminoacid sequence having at least 90% identity to SEQ ID NOS:256 and 267,respectively; or a V_(H) region and a V_(L) regions comprising the aminoacid sequence having at least 90% identity to SEQ ID NOS:519 and 535,respectively. In some of any embodiments, the antibody orantigen-binding fragment comprises a V_(H) region and a V_(L) regionscomprising the amino acid sequence having at least 90% identity to SEQID NOs:115 and 536, respectively.

In some embodiments, antibodies or antigen-binding fragments thereofcomprise a V_(H) region sequence that is at least at or about 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to such a SEQ ID NOand/or a V_(L) region sequence that is at least at or about 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to such a SEQ ID NO.

In some embodiments, the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:110 and 116, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:111 and 117,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:110 and 118, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:110 and 119,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:110 and 120, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:110 and 121,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:110 and 122, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:110 and 123,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:112 and 124, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:113 and 125,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:114 and 126, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:115 and 127,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:247 and 257, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:248 and 258,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:249 and 259, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:250 and 260,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:251 and 261, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:252 and 262,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:253 and 263, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:254 and 264,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:255 and 265, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:256 and 266,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:256 and 267, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:518 and 534,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:519 and 535, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:115 and 536,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:520 and 264, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:521 and 537,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:522 and 538, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:523 and 539,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:519 and 540, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:524 and 541,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:525 and 261, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:526 and 542,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:527 and 543, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:528 and 544,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:529 and 545, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:528 and 546,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:522 and 547, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:256 and 548,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:530 and 549, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:531 and 550,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:519 and 552, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:110 and 553,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:110 and 118, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:533 and 554,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:115 and 555, respectively; the V_(H) and V_(L)regions comprise the amino acid sequences of SEQ ID NOs:524 and 556,respectively; or the V_(H) and V_(L) regions comprise the amino acidsequences of SEQ ID NOs:519 and 557, respectively.

In some of any embodiments, the V_(H) and V_(L) regions of the antibodyor antigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:110 and 116, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the amino acidsequences of SEQ ID NOs:110 and 120, respectively; the V_(H) and V_(L)regions of the antibody or antigen-binding fragment thereof comprise theamino acid sequences of SEQ ID NOS:256 and 267, respectively; or theV_(H) and V_(L) regions of the antibody or antigen-binding fragmentthereof comprise the amino acid sequences of SEQ ID NOS:519 and 535,respectively. In some of any embodiments, the V_(H) and V_(L) regions ofthe antibody or antigen-binding fragment thereof comprise the amino acidsequences of SEQ ID NOs:115 and 536, respectively.

In some of any such embodiments, the antibody or antigen-bindingfragment thereof specifically binds to a BCMA protein. In someembodiments, the BCMA protein is a human BCMA protein, a mouse BCMAprotein, or a non-human primate BCMA protein. In some embodiments, theBCMA protein is a human BCMA protein. In some embodiments, the antibodyor antigen-binding fragment further specifically binds to a mouse BCMAor a non-human primate BCMA. In some embodiments, the human BCMA proteincomprises an amino acid sequence of SEQ ID NO:367 or 368.

In some of any such embodiments, the antibody or antigen-bindingfragment thereof has a binding affinity for a BCMA protein with an EC₅₀that is from or from about 0.1 nM to 400 nM, from or from about 0.5 nMto 200 nM, from or from about 1 nM to 100 nM, or from or from about 2 nMto 50 nM; or the antibody or antigen-binding fragment has a bindingaffinity for a BCMA protein with an EC₅₀ that is less than or less thanabout 400 nM, less than or less than about 300 nM, less than or lessthan about 200 nM, less than or less than about 100 nM, less than orless than about 50 nM, less than or less than about 25 nM or less thanor less than about 5 nM.

In some of any such embodiments, the binding affinity of said antibodyor antigen-binding fragment to a human BCMA protein is at least as highor substantially as high as the binding affinity of an antibodycomprising the amino acid sequence of SEQ ID NOS:328, 329, 585 and/or586 to the human BCMA. In some of any such embodiments, said antibody orantigen-binding fragment competes for binding to a human BCMA proteinwith an antibody comprising the amino acid sequence of SEQ ID NOs:328,329, 585 and/or 586. In some of any such embodiments, said antibody orantigen-binding fragment specifically binds to the same or anoverlapping epitope of a human BCMA protein as an antibody comprisingthe amino acid sequence of SEQ ID NOs:328, 329, 585 and/or 586.

In some of any such embodiments, said antibody or antigen-bindingfragment does not compete for binding to a human BCMA protein with anantibody comprising the amino acid sequence of SEQ ID NOs:328, 329, 585and/or 586. In some of any such embodiments, said antibody orantigen-binding fragment specifically binds to a different epitope of ahuman BCMA protein as an antibody comprising the amino acid sequence ofSEQ ID NOs:328, 329, 585 and/or 586. In some of any such embodiments,said antibody or antigen-binding fragment inhibits the binding of anantibody comprising the amino acid sequence of SEQ ID NO:328, 329, 585and/or 586 to a human BCMA protein by greater than or greater than about80% or greater than or greater than about 90%. In some of any suchembodiments, said human BCMA protein comprises an amino acid sequence ofSEQ ID NO:367 or 368.

In some of any such embodiments, the antibody does not comprise CDR-H1,CDR-H2, CDR-H3, CDR-L1, CDR-L2 and/or CDR-L3 sequences having at least90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to theCDR-H1, CDR-H2, CDR-H3 and/or CDR-L1, CDR-L2, CDR-L3 sequences containedwithin an antibody comprising the amino acid sequence of SEQ ID NOs:328,329, 585 and/or 586. In some of any such embodiments, the antibody doesnot comprise the CDR-H1, CDR-H2, CDR-H3 and/or CDR-L1, CDR-L2, CDR-L3sequences contained within an antibody comprising the amino acidsequence of SEQ ID NO:328 and/or an antibody comprising the amino acidsequence of SEQ ID NO:329, and/or an antibody comprising the amino acidsequence of SEQ ID NO:585, and/or an antibody comprising the amino acidsequence of SEQ ID NO:586. In some of any such embodiments, the antibodyor antigen-binding fragment is human.

Provided herein are human antibodies or antigen-binding fragmentsthereof that specifically binds to the same or an overlapping epitope ofa BCMA protein, which optionally is human BCMA, as the epitopespecifically bound by a reference antibody, wherein the referenceantibody is the antibody or antigen-binding fragment thereof or anantibody comprising the amino acid sequence of SEQ ID NOs:328, 329, 585and/or 586, said human antibody or antigen-binding fragment comprisingheavy and light chain CDRs that are distinct from the heavy and lightchain CDRs contained within the antibody comprising the amino acidsequence of SEQ ID NOs:328, 329, 585 and/or 586.

Provided herein are human antibodies or antigen-binding fragmentsthereof that specifically binds to BCMA and competes for binding to BCMAwith a reference antibody, which BCMA is optionally human BCMA, whereinthe reference antibody is the antibody or antigen-binding fragment or anantibody comprising the amino acid sequence of SEQ ID NOs:328, 329, 585and/or 586, said human antibody or antigen-binding fragment comprisingheavy and light chain CDRs that are distinct from the heavy and lightchain CDRs contained within the antibody comprising the amino acidsequence of SEQ ID NOs:328, 329, 585 and/or 586.

In some of any such embodiments, the human antibody or antigen-bindingfragment thereof comprises a V_(H) region, said V_(H) region comprisinga portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequenceidentity to an amino acid sequence encoded by a germline nucleotidehuman heavy chain V segment, a portion with at least 95%, 96%, 97%, 98%,99%, or 100% sequence identity to an amino acid sequence encoded by agermline nucleotide human heavy chain D segment, and/or a portion havingat least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an aminoacid sequence encoded by a germline nucleotide human heavy chain Jsegment; and/or the antibody or antigen-binding fragment comprises aV_(L) region, said V_(L) region comprising a portion with at least 95%,96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequenceencoded by a germline nucleotide human kappa or lambda chain V segment,and/or a portion with at least 95%, 96%, 97%, 98%, 99%, or 100% sequenceidentity to an amino acid sequence encoded by a germline nucleotidehuman kappa or lambda chain J segment.

In some of any such embodiments, the human antibody or antigen-bindingfragment thereof contains a CDR-H1 and/or CDR-H2 comprising a sequence100% identical or with no more than one amino acid difference ascompared to an amino acid sequence of a CDR-H1 and/or CDR-H2,respectively, within a sequence encoded by a germline nucleotide humanheavy chain V segment; and/or contains a CDR-L1 and/or CDR-L2 comprisinga sequence 100% identical or with no more than one amino acid differenceas compared to an amino acid sequence of a CDR-L1 and/or CDR-L2,respectively, within a sequence encoded by a germline nucleotide humankappa or lambda v segment.

In some of any such embodiments, the antibody or antigen-bindingfragment is recombinant. In some of any such embodiments, the antibodyor antigen-binding fragment is monoclonal. In some of any suchembodiments, the antibody or antigen-binding fragment is anantigen-binding fragment. In some of any such embodiments, the antibodyor antigen-binding fragment is a single chain fragment.

In some of any such embodiments, the antibody is a fragment comprisingV_(H) and V_(L) regions joined by a flexible linker. In some of any suchembodiments, the fragment comprises an scFv. In some embodiments, thescFv comprises a linker comprising the amino acid sequenceGGGGSGGGGSGGGGS (SEQ ID NO:361). In some embodiments, the scFv comprisesthe amino acid sequence selected from any one of SEQ ID NOs:128-139,268-278, 558-576 and 578-583, or an amino acid sequence having at least90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity tothe amino acid sequence selected from any one of SEQ ID NOs:128-139,268-278, 558-576 and 578-583.

In some of any embodiments, the scFv comprises the amino acid sequenceselected from any one of SEQ ID NOs: 128, 132, 278 and 502, or an aminoacid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity to the amino acid sequence selected fromany one of SEQ ID NOs: 128, 132, 278 and 502. In some of anyembodiments, the scFv comprises the amino acid sequence of SEQ IDNO:560, or an amino acid sequence having at least 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acidsequence of SEQ ID NO:560.

In some embodiments, the receptor includes an antigen-binding domainthat binds to the same or substantially the same epitope on BCMA, orcompetes for binding to BCMA with, any of the antibodies and fragments,or antibodies having the provided combinations of V_(H)/V_(L) or CDRsequences, described herein including in any of the foregoingembodiments. In some embodiments, the binding domain recognizes anepitope comprising a portion of one or more amino acid sequences withina BCMA polypeptide. In some aspects, such one or more amino acidsequences are or comprise: MLMAG (SEQ ID NO:616), YFDSL (SEQ ID NO:618),and QLRCSSNTPPL (SEQ ID NO:619). In some aspects, such one or more aminoacid sequences are or comprise: MLMAG (SEQ ID NO:616), YFDSLL (SEQ IDNO:620), and QLRCSSNTPPL (SEQ ID NO:619). In some aspects, such one ormore amino acid sequences are or comprise: MLMAG (SEQ ID NO:616),QNEYFDSLL (SEQ ID NO:617), and QLRCSSNTPPL (SEQ ID NO:619). In someaspects, such one or more amino acid sequences are or comprise: QNEYF(SEQ ID NO:613), CIPCQL (SEQ ID NO:614), and CQRYC (SEQ ID NO:615). Insome aspects, such one or more amino acid sequences are or comprise:CSQNEYF (set forth in SEQ ID NO:611) and LLHACIPCQLR (set forth in SEQID NO:612).

Also provided herein is a single chain cell-surface protein comprisingany of the single chain antibody fragments provided herein. In someembodiments, the single chain cell surface protein contains any of theprovided single domain antibodies.

Provided is a single chain cell-surface protein comprising the scFvamino acid sequence selected from any one of SEQ ID NOs:128-139,268-278, 558-576 and 578-583 or comprising the V_(H) region amino acidsequence selected from any one of SEQ ID NOs:110-115, 247-256, 518-531and 533. Also provided herein are single chain cell surface proteinscomprising the scFv amino acid sequence selected from any one of SEQ IDNOs:128-139, 268-278, 558-576 and 578-583. In some of any suchembodiments, the scFv comprises the amino acid sequence selected fromany one of SEQ ID NOs:128, 132, 278 and 502. In some of any suchembodiments, the scFv comprises the amino acid sequence of SEQ IDNO:560.

In some of any such embodiments, the antibody or antigen-bindingfragment further comprises at least a portion of an immunoglobulinconstant region. In some embodiments, the portion of an immunoglobulinconstant region comprises at least a portion of the hinge region. Insome embodiments, the portion of an immunoglobulin constant regioncomprises an Fc region. In some embodiments, the Fc region is an Fcregion of a human IgG.

Also provided is a conjugate comprising any of the provided antibodiesor antigen-binding fragments and a heterologous molecule or moiety. Alsoprovided is a conjugate containing any of the provided single chaincell-surface proteins.

Also provided is a chimeric antigen receptor (CAR) including anextracellular portion containing any of the provided antibodies orantigen-binding fragments and an intracellular signaling domain. In someembodiments, the antibody or antigen-binding fragment comprises a V_(H)only domain (e.g., an sdAb) or an scFv and the intracellular signalingdomain comprises an ITAM. In some embodiments, the intracellularsignaling domain comprises a signaling domain of a zeta chain of aCD3-zeta (CD3ζ) chain, optionally a human CD3ζ or a signaling portionthereof.

In some of any such embodiments, the CAR further comprises atransmembrane domain linking the extracellular domain and theintracellular signaling domain. In some embodiments, the transmembranedomain comprises a transmembrane portion of a costimulatory molecule,such as a T cell costimulatory molecule, e.g., CD28 and/or 4-1BB,optionally a human CD28. In some embodiments, the T cell costimulatorymolecule is CD28 or 4-1BB. In some embodiments, the intracellularsignaling domain also includes an intracellular domain of a T cellcostimulatory molecule. In some aspects, the T cell costimulatorymolecule is CD28 or 4-1BB. In some embodiments, the costimulatorysignaling domain comprises an intracellular signaling domain of a 4-1BB,optionally a human 4-1BB.

In some embodiments of any of the provided CARs, the CAR contains anantibody or antigen-binding fragment thereof as provided herein, atransmembrane domain that is a portion of CD28 or variant thereof, andan intracellular signaling domain containing a signaling portion of CD28or functional variant thereof and a signaling portion of CD3 zeta orfunctional variant thereof. In some of any such embodiments, the CARfurther includes a spacer containing an Ig hinge, e.g., an IgG4 hinge,such as a hinge-only spacer. In some of any such embodiments, the CARfurther includes a truncated EGFR sequence. In some of any suchembodiments, the CAR further includes an Ig kappa signal sequence and/ora CD33 signal sequence.

In some embodiments of any of the provided CARs, the CAR contains anantibody or antigen-binding fragment thereof as provided herein, atransmembrane domain that is a portion of CD28 or variant thereof, andan intracellular signaling domain containing a signaling portion of a4-1BB or functional variant thereof and a signaling portion of CD3 zetaor functional variant thereof. In some such embodiments, the CAR furtherincludes a spacer containing an Ig hinge, e.g., an IgG4 hinge, such as ahinge-only spacer. In some of any such embodiments, the CAR furtherincludes a truncated EGFR sequence. In some of any such embodiments, theCAR further includes an Ig kappa signal sequence and/or a CD33 signalsequence.

Further provided herein are nucleic acids encoding any of the providedantibodies or antigen-binding fragments thereof, any of the providedsingle chain cell-surface proteins, any of the provided conjugates, orany of the provided CARs. In some embodiments, the nucleic acid furtherencodes a GM-CSF signal sequence, a CD8 signal sequence, an Ig kappasignal sequence or a CD33 signal sequence.

Also provided are vectors comprising a nucleic acid provided herein. Insome embodiments, the vector is an expression vector. In some of anysuch embodiments, the vector is a viral vector. In some of any suchembodiments, the vector is a retroviral vector. In some of any suchembodiments, the viral vector is a lentiviral vector. In some of anysuch embodiments, the lentiviral vector is derived from HIV-1.

Provided herein are cells that contain any of the provided antibodies orantigen-binding fragments thereof, any of the provided single chaincell-surface proteins, any of the provided conjugates, or any of theprovided CARs. In some embodiments, the cell is an engineered cellexpressing a receptor (e.g., a chimeric antigen receptor) comprising anyof the provided antibodies or antigen-binding fragments thereof, any ofthe provided single chain cell-surface proteins, any of the providedconjugates, or any of the provided CARs. In some embodiments, the cellor engineered cell is a T cell. Also provided are engineered cellscomprising a vector provided herein.

Provided are compositions or pharmaceutical compositions comprising anyof the provided antibodies or antigen-binding fragments thereof, any ofthe provided single chain cell-surface proteins, any of the providedconjugates, any of the provided CARs or any of the provided cells. Insome embodiments, the composition or pharmaceutical composition containsa pharmaceutically acceptable excipient.

Provided herein are also methods of treatment that include administeringany one or more of the provided compositions or pharmaceuticalcompositions to a subject having a disease or disorder associated withBCMA. Provided are methods of treatment that include administering anyof the provided antibodies or antigen-binding fragments, any of theprovided single chain cell-surface proteins, any of the providedconjugates, any of the provided CARs or any of the provided cells (e.g.,engineered T cell) to a subject having a disease or disorder associatedwith BCMA.

Provided herein are any of the provided compositions or pharmaceuticalcompositions for use in treating a disease or disorder associated withBCMA. Provided is use of any of the provided compositions orpharmaceutical compositions for the manufacture of a medicament fortreating a disease or disorder associated with BCMA. Also providedherein are use of any of the compositions or pharmaceutical compositionsdescribed herein for the treatment of a disease or disorder associatedwith BCMA. In some embodiments, a composition or pharmaceuticalcomposition provided herein comprises any of the provided antibodies orantigen-binding fragments, any of the provided single chain cell-surfaceproteins, any of the provided conjugates, any of the provided CARs orany of the provided cells (e.g., engineered T cell).

In some of any such embodiments, the disease or disorder associated withBCMA is associated with BCMA expression. In some of any suchembodiments, the disease or disorder associated with BCMA is a Bcell-related disorder. In some of any such embodiments, the disease ordisorder associated with BCMA is an autoimmune disease or disorder. Insome embodiments, the autoimmune disease or disorder is systemic lupuserythematosus (SLE), lupus nephritis, inflammatory bowel disease,rheumatoid arthritis (e.g., juvenile rheumatoid arthritis), ANCAassociated vasculitis, idiopathic thrombocytopenia purpura (ITP),thrombotic thrombocytopenia purpura (TTP), autoimmune thrombocytopenia,Chagas' disease, Grave's disease, Wegener's granulomatosis,poly-arteritis nodosa, Sjogren's syndrome, pemphigus vulgaris,scleroderma, multiple sclerosis, psoriasis, IgA nephropathy, IgMpolyneuropathies, vasculitis, diabetes mellitus, Reynaud's syndrome,anti-phospholipid syndrome, Goodpasture's disease, Kawasaki disease,autoimmune hemolytic anemia, myasthenia gravis, or progressiveglomerulonephritis.

In some of any such embodiments, the disease or disorder associated withBCMA is a cancer. In some embodiments, the cancer is a BCMA-expressingcancer. In some embodiments, the cancer is a B cell malignancy. In anyof such embodiments, the cancer is a lymphoma, a leukemia, or a plasmacell malignancy. In some embodiments, the lymphoma is Burkitt lymphoma(e.g., endemic Burkitt's lymphoma or sporadic Burkitt's lymphoma),non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, Waldenstrommacroglobulinemia, follicular lymphoma, small non-cleaved cell lymphoma,mucosa-associated lymphatic tissue lymphoma (MALT), marginal zonelymphoma, splenic lymphoma, nodal monocytoid B cell lymphoma,immunoblastic lymphoma, large cell lymphoma, diffuse mixed celllymphoma, pulmonary B cell angiocentric lymphoma, small lymphocyticlymphoma, primary mediastinal B cell lymphoma, lymphoplasmacyticlymphoma (LPL), or mantle cell lymphoma (MCL). In some embodiments, theleukemia is chronic lymphocytic leukemia (CLL), plasma cell leukemia oracute lymphocytic leukemia (ALL). In some embodiments, the plasma cellmalignancy is multiple myeloma (e.g., non-secretory multiple myeloma,smoldering multiple myeloma) or plasmacytoma. In some of the embodimentsherein, the disease or disorder associated with BCMA is one or more ofglioblastoma, lymphomatoid granulomatosis, post-transplantlymphoproliferative disorder, an immunoregulatory disorder, heavy-chaindisease, primary or immunocyte-associated amyloidosis, and monoclonalgammopathy of undetermined significance.

It is to be understood that one, some, or all of the properties of thevarious embodiments described herein may be combined to form otherembodiments of the present invention. These and other aspects of theinvention will become apparent to one of skill in the art. These andother embodiments of the invention are further described by the detaileddescription that follows.

DETAILED DESCRIPTION

Provided are BCMA-binding molecules, including antibodies (includingantigen-binding antibody fragments, such as heavy chain variable (V_(H))regions and single chain fragments, including scFvs) and recombinantreceptors, including chimeric receptors and single chain cell surfaceproteins containing such antibodies and antigen-binding fragments,nucleic acids encoding such antibodies and antigen-binding fragments andreceptors, and cells, such as recombinant or engineered cells forexpressing and production of these antibodies and antigen-bindingfragments or receptors. Also provided are methods of making and usingthe antibodies and antigen-binding fragments as well as cells (e.g.,engineered cells) expressing or containing the antibodies andantigen-binding fragments or receptors. Also provided are compositions,including pharmaceutical compositions, containing such antibodies,antigen-binding fragments, receptors or cells. In some aspects, theprovided compositions, antibodies, antigen-binding fragments, receptorsor cells can be used in connection with a therapy or a method oftreatment.

All publications, including patent documents, scientific articles anddatabases, referred to in this application are incorporated by referencein their entirety for all purposes to the same extent as if eachindividual publication were individually incorporated by reference. If adefinition set forth herein is contrary to or otherwise inconsistentwith a definition set forth in the patents, applications, publishedapplications and other publications that are herein incorporated byreference, the definition set forth herein prevails over the definitionthat is incorporated herein by reference.

The section heading used herein are for organizational purposes only andare not to be construed as limiting the subject matter described.

I. BCMA-BINDING MOLECULES

Provided in some aspects are BCMA-binding molecules, such asBCMA-binding polypeptides. Such binding molecules include antibodies(including antigen-binding fragments) that specifically bind to BCMAproteins, such as a human BCMA protein. Also among the binding moleculesare polypeptides containing such antibodies, including single chain cellsurface proteins, e.g., recombinant receptors such as chimeric antigenreceptors (CARs), containing such antibodies.

A. BCMA Antibodies

Provided are anti-BCMA antibodies, including functional antigen-bindingfragments. In some embodiments, the antibodies or antigen-bindingfragments include those that are single domain antibodies, containing aheavy chain variable (V_(H)) region that, without pairing with a lightchain antigen-binding site (e.g., light chain variable (V_(L)) region)and/or without any additional antibody domain or binding site, arecapable of specifically binding to BCMA. Also among the antibodies orantigen-binding fragments are multi-domain antibodies, such as thosecontaining V_(H) and V_(L) domains, comprised of the V_(H) domain orantigen-binding site thereof of the single-domain antibody. In someembodiments, the antibodies or antigen-binding fragments include a heavychain variable region and a light chain variable region, such as scFvs.The antibodies include antibodies that specifically bind to BCMA, e.g.,human BCMA. Among the provided anti-BCMA antibodies are humanantibodies. The antibodies include isolated antibodies. Also providedare BCMA-binding molecules containing such antibodies, e.g.,single-chain proteins, fusion proteins, and/or recombinant receptorssuch as chimeric receptors, including antigen receptors. TheBCMA-binding molecules include isolated molecules.

The term “antibody” herein is used in the broadest sense and includespolyclonal and monoclonal antibodies, including intact antibodies andfunctional (antigen-binding) antibody fragments, including fragmentantigen binding (Fab) fragments, F(ab′)2 fragments, Fab′ fragments, Fvfragments, recombinant IgG (rIgG) fragments, heavy chain variable(V_(H)) regions capable of specifically binding the antigen, singlechain antibody fragments, including single chain variable fragments(scFv), and single domain antibodies (e.g., sdAb, sdFv, nanobody)fragments. The term encompasses genetically engineered and/or otherwisemodified forms of immunoglobulins, such as intrabodies, peptibodies,chimeric antibodies, fully human antibodies, humanized antibodies, andheteroconjugate antibodies, multispecific, e.g., bispecific ortrispecific, antibodies, diabodies, triabodies, and tetrabodies, tandemdi-scFv, tandem tri-scFv. Unless otherwise stated, the term “antibody”should be understood to encompass functional antibody fragments thereofalso referred to herein as “antigen-binding fragments.” The term alsoencompasses intact or full-length antibodies, including antibodies ofany class or sub-class, including IgG and sub-classes thereof, IgM, IgE,IgA, and IgD.

The terms “complementarity determining region,” and “CDR,” synonymouswith “hypervariable region” or “HVR,” are known in the art to refer tonon-contiguous sequences of amino acids within antibody variableregions, which confer antigen specificity and/or binding affinity. Ingeneral, there are three CDRs in each heavy chain variable region(CDR-H1, CDR-H2, CDR-H3) and three CDRs in each light chain variableregion (CDR-L1, CDR-L2, CDR-L3). “Framework regions” and “FR” are knownin the art to refer to the non-CDR portions of the variable regions ofthe heavy and light chains. In general, there are four FRs in eachfull-length heavy chain variable region (FR-H1, FR-H2, FR-H3, andFR-H4), and four FRs in each full-length light chain variable region(FR-L1, FR-L2, FR-L3, and FR-L4).

The precise amino acid sequence boundaries of a given CDR or FR can bereadily determined using any of a number of well-known schemes,including those described by Kabat et al. (1991), “Sequences of Proteinsof Immunological Interest,” 5th Ed. Public Health Service, NationalInstitutes of Health, Bethesda, MD (“Kabat” numbering scheme);Al-Lazikani et al., (1997) JMB 273,927-948 (“Chothia” numbering scheme);MacCallum et al., J. Mol. Biol. 262:732-745 (1996), “Antibody-antigeninteractions: Contact analysis and binding site topography,” J. Mol.Biol. 262, 732-745.” (“Contact” numbering scheme); Lefranc M P et al.,“IMGT unique numbering for immunoglobulin and T cell receptor variabledomains and Ig superfamily V-like domains,” Dev Comp Immunol, 2003January; 27(1):55-77 (“IMGT” numbering scheme); Honegger A and PlückthunA, “Yet another numbering scheme for immunoglobulin variable domains: anautomatic modeling and analysis tool,” J Mol Biol, 2001 Jun. 8;309(3):657-70, (“Aho” numbering scheme); and Martin et al., “Modelingantibody hypervariable loops: a combined algorithm,” PNAS, 1989,86(23):9268-9272, (“AbM” numbering scheme).

The boundaries of a given CDR or FR may vary depending on the schemeused for identification. For example, the Kabat scheme is based onstructural alignments, while the Chothia scheme is based on structuralinformation. Numbering for both the Kabat and Chothia schemes is basedupon the most common antibody region sequence lengths, with insertionsaccommodated by insertion letters, for example, “30a,” and deletionsappearing in some antibodies. The two schemes place certain insertionsand deletions (“indels”) at different positions, resulting indifferential numbering. The Contact scheme is based on analysis ofcomplex crystal structures and is similar in many respects to theChothia numbering scheme. The AbM scheme is a compromise between Kabatand Chothia definitions based on that used by Oxford Molecular's AbMantibody modeling software.

Table 1, below, lists exemplary position boundaries of CDR-L1, CDR-L2,CDR-L3 and CDR-H1, CDR-H2, CDR-H3 as identified by Kabat, Chothia, AbM,and Contact schemes, respectively. For CDR-H1, residue numbering islisted using both the Kabat and Chothia numbering schemes. FRs arelocated between CDRs, for example, with FR-L1 located before CDR-L1,FR-L2 located between CDR-L1 and CDR-L2, FR-L3 located between CDR-L2and CDR-L3 and so forth. It is noted that because the shown Kabatnumbering scheme places insertions at H35A and H35B, the end of theChothia CDR-H1 loop when numbered using the shown Kabat numberingconvention varies between H32 and H34, depending on the length of theloop.

TABLE 1 Boundaries of CDRs according to various numbering schemes. CDRKabat Chothia AbM Contact CDR-L1 L24--L34 L24--L34 L24--L34 L30--L36CDR-L2 L50--L56 L50--L56 L50--L56 L46--L55 CDR-L3 L89--L97 L89--L97L89--L97 L89--L96 CDR-H1 H31--H35B H26--H32 . . . H26--H35B H30--H35B(Kabat 34 Numbering¹) CDR-H1 H31--H35 H26--H32 H26--H35 H30--H35(Chothia Numbering²) CDR-H2 H50--H65 H52--H56 H50--H58 H47--H58 CDR-H3H95--H102 H95--H102 H95--H102 H93--H101 ¹Kabat et al. (1991), “Sequencesof Proteins of Immunological Interest,” 5th Ed. Public Health Service,National Institutes of Health, Bethesda, MD ²Al-Lazikani et al., (1997)JMB 273, 927-948

Thus, unless otherwise specified, a “CDR” or “complementary determiningregion,” or individual specified CDRs (e.g., CDR-H1, CDR-H2, CDR-H3), ofa given antibody or region thereof, such as a variable region thereof,should be understood to encompass a (or the specific) complementarydetermining region as defined by any of the aforementioned schemes, orother known schemes. For example, where it is stated that a particularCDR (e.g., a CDR-H3) contains the amino acid sequence of a correspondingCDR in a given V_(H) or V_(L) region amino acid sequence, it isunderstood that such a CDR has a sequence of the corresponding CDR(e.g., CDR-H3) within the variable region, as defined by any of theaforementioned schemes, or other known schemes. In some embodiments,specific CDR sequences are specified. Exemplary CDR sequences ofprovided antibodies are described using various numbering schemes (seee.g. Table 2, Table 3 and Table 4), although it is understood that aprovided antibody can include CDRs as described according to any of theother aforementioned numbering schemes or other numbering schemes knownto a skilled artisan.

Likewise, unless otherwise specified, a FR or individual specified FR(s)(e.g., FR-H1, FR-H2, FR-H3, FR-H4), of a given antibody or regionthereof, such as a variable region thereof, should be understood toencompass a (or the specific) framework region as defined by any of theknown schemes. In some instances, the scheme for identification of aparticular CDR, FR, or FRs or CDRs is specified, such as the CDR asdefined by the Kabat, Chothia, AbM or Contact method, or other knownschemes. In other cases, the particular amino acid sequence of a CDR orFR is given.

The term “variable region” or “variable domain” refers to the domain ofan antibody heavy or light chain that is involved in binding theantibody to antigen. The variable regions of the heavy chain and lightchain (V_(H) and V_(L), respectively) of a native antibody generallyhave similar structures, with each domain comprising four conservedframework regions (FRs) and three CDRs. (See, e.g., Kindt et al. KubyImmunology, 6th ed., W.H. Freeman and Co., page 91 (2007). A singleV_(H) or V_(L) domain may be sufficient to confer antigen-bindingspecificity. Furthermore, antibodies that bind a particular antigen maybe isolated using a V_(H) or V_(L) domain from an antibody that bindsthe antigen to screen a library of complementary V_(L) or V_(H) domains,respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887(1993); Clarkson et al., Nature 352:624-628 (1991).

Among the provided antibodies are antibody fragments. An “antibodyfragment” or “antigen-binding fragment” refers to a molecule other thanan intact antibody that comprises a portion of an intact antibody thatbinds the antigen to which the intact antibody binds. Examples ofantibody fragments include but are not limited to Fv, Fab, Fab′,Fab′-SH, F(ab′)2; diabodies; linear antibodies; heavy chain variable(V_(H)) regions, single-chain antibody molecules such as scFvs andsingle-domain antibodies comprising only the V_(H) region; andmultispecific antibodies formed from antibody fragments. In someembodiments, the antibody is or comprises an antibody fragmentcomprising a variable heavy chain (V_(H)) and a variable light chain(V_(L)) region. In particular embodiments, the antibodies aresingle-chain antibody fragments comprising a heavy chain variable(V_(H)) region and/or a light chain variable (V_(L)) region, such asscFvs.

Single-domain antibodies (sdAbs) are antibody fragments comprising allor a portion of the heavy chain variable region or all or a portion ofthe light chain variable region of an antibody. In certain embodiments,a single-domain antibody is a human single-domain antibody.

Antibody fragments can be made by various techniques, including but notlimited to proteolytic digestion of an intact antibody as well asproduction by recombinant host cells. In some embodiments, theantibodies are recombinantly-produced fragments, such as fragmentscomprising arrangements that do not occur naturally, such as those withtwo or more antibody regions or chains joined by synthetic linkers,e.g., peptide linkers, and/or that are may not be produced by enzymedigestion of a naturally-occurring intact antibody. In some aspects, theantibody fragments are scFvs.

A “humanized” antibody is an antibody in which all or substantially allCDR amino acid residues are derived from non-human CDRs and all orsubstantially all FR amino acid residues are derived from human FRs. Ahumanized antibody optionally may include at least a portion of anantibody constant region derived from a human antibody. A “humanizedform” of a non-human antibody, refers to a variant of the non-humanantibody that has undergone humanization, typically to reduceimmunogenicity to humans, while retaining the specificity and affinityof the parental non-human antibody. In some embodiments, some FRresidues in a humanized antibody are substituted with correspondingresidues from a non-human antibody (e.g., the antibody from which theCDR residues are derived), e.g., to restore or improve antibodyspecificity or affinity.

Among the provided anti-BCMA antibodies are human antibodies. A “humanantibody” is an antibody with an amino acid sequence corresponding tothat of an antibody produced by a human or a human cell, or non-humansource that utilizes human antibody repertoires or other humanantibody-encoding sequences, including human antibody libraries. Theterm excludes humanized forms of non-human antibodies comprisingnon-human antigen-binding regions, such as those in which all orsubstantially all CDRs are non-human. The term includes antigen-bindingfragments of human antibodies.

Human antibodies may be prepared by administering an immunogen to atransgenic animal that has been modified to produce intact humanantibodies or intact antibodies with human variable regions in responseto antigenic challenge. Such animals typically contain all or a portionof the human immunoglobulin loci, which replace the endogenousimmunoglobulin loci, or which are present extrachromosomally orintegrated randomly into the animal's chromosomes. In such transgenicanimals, the endogenous immunoglobulin loci have generally beeninactivated. Human antibodies also may be derived from human antibodylibraries, including phage display and cell-free libraries, containingantibody-encoding sequences derived from a human repertoire.

Among the provided antibodies are monoclonal antibodies, includingmonoclonal antibody fragments. The term “monoclonal antibody” as usedherein refers to an antibody obtained from or within a population ofsubstantially homogeneous antibodies, i.e., the individual antibodiescomprising the population are identical, except for possible variantscontaining naturally occurring mutations or arising during production ofa monoclonal antibody preparation, such variants generally being presentin minor amounts. In contrast to polyclonal antibody preparations, whichtypically include different antibodies directed against differentepitopes, each monoclonal antibody of a monoclonal antibody preparationis directed against a single epitope on an antigen. The term is not tobe construed as requiring production of the antibody by any particularmethod. A monoclonal antibody may be made by a variety of techniques,including but not limited to generation from a hybridoma, recombinantDNA methods, phage-display and other antibody display methods.

The terms “polypeptide” and “protein” are used interchangeably to referto a polymer of amino acid residues, and are not limited to a minimumlength. Polypeptides, including the provided antibodies and antibodychains and other peptides, e.g., linkers and BCMA-binding peptides, mayinclude amino acid residues including natural and/or non-natural aminoacid residues. The terms also include post-expression modifications ofthe polypeptide, for example, glycosylation, sialylation, acetylation,phosphorylation, and the like. In some aspects, the polypeptides maycontain modifications with respect to a native or natural sequence, aslong as the protein maintains the desired activity. These modificationsmay be deliberate, as through site-directed mutagenesis, or may beaccidental, such as through mutations of hosts which produce theproteins or errors due to PCR amplification.

a. Exemplary Antibodies

In some embodiments, the antibody, e.g., the anti-BCMA antibody orantigen-binding fragment thereof, contains a heavy and/or light chainvariable (V_(H) and/or V_(L)) region sequence as described, or asufficient antigen-binding portion thereof. In some embodiments, theanti-BCMA antibody or antigen-binding fragment thereof, contains a V_(H)region sequence or sufficient antigen-binding portion thereof thatcontains a CDR-H1, CDR-H2 and/or CDR-H3 as described. In someembodiments, the anti-BCMA antibody or antigen-binding fragment thereof,contains a V_(L) region sequence or sufficient antigen-binding portionthat contains a CDR-L1, CDR-L2 and/or CDR-L3 as described. In someembodiments, the anti-BCMA antibody or antigen-binding fragment thereof,contains a V_(H) region sequence that contains a CDR-H1, CDR-H2 and/orCDR-H3 as described and contains a V_(L) region sequence that contains aCDR-L1, CDR-L2 and/or CDR-L3 as described. Also among the providedantibodies are those having sequences at least at or about 90%, about91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%,about 98%, or about 99% identical to such a sequence.

In some embodiments, the antibody, e.g., antigen-binding fragmentthereof, has a heavy chain variable (V_(H)) region having the amino acidsequence selected from any one of SEQ ID NOs:110-115, 247-256, 518-531and 533, or an amino acid sequence that has at least 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the V_(H) regionamino acid selected from any one of SEQ ID NOs:110-115, 247-256, 518-531and 533, or contains a CDR-H1, +CDR-H2, and/or CDR-H3 present in such aV_(H) sequence.

In some embodiments, the V_(H) region of the anti-BCMA antibody is onethat includes a heavy chain complementarity determining region 3(CDR-H3) comprising the amino acid sequenceX₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃X₁₄ (SEQ ID NO:355), wherein Xi is A, D,E, G, L, V or W; X₂ is A, D, G, L, P, Q or S; X₃ is A, D, G, L or Y; X₄is D, G, P, R, S, V, Y or null; X₅ is D, I, P, S, T, Y or null; X₆ is A,G, I, S, T, V, Y or null; X₇ is A, D, E, F, L, P, S, Y or null; X₈ is P,Q, T, Y or null; X₉ is D, G, R, Y or null; X₁₀ is A, F, Y or null; X₁₁is D, F or null; X₁₂ is F or null; X₁₃ is D, T or Y; and X₁₄ is I, L, N,V or Y. In some such embodiments, in said CDR-H3, Xi is V; X₂ is D; X₃is G; X₄ is D; X₅ is Y; X₆ is V; X₇ is D; X₈ is null; X₉ is null; X₁₀ isnull; X₁₁ is null; X₁₂ is null; X₁₃ is D; and X₁₄ is Y.

In some embodiments, the provided antibody or antigen-binding fragmentthereof comprises a CDR-H3 comprising the amino acid sequence selectedfrom any one of SEQ ID NOs:7-11, 149-157, 279-287 and 376-378 accordingto Kabat numbering. In some embodiments, the V_(H) region of a providedantibody or antigen-binding fragment thereof contains a CDR-H3 havingthe amino acid sequence comprising the amino acid sequence selected fromany one of SEQ ID NOs:7-11, 149-157, 279-287 and 376-378 according toChothia numbering or AbM numbering. In some embodiments, the providedantibody or antigen-binding fragment thereof contains a CDR-H3 havingthe amino acid sequence of SEQ ID NO:9 according to Kabat numbering,Chothia numbering or AbM numbering. In any of such examples, theprovided antibody or antigen-binding fragment thereof can contain aV_(H) region sequence selected from any one of SEQ ID NOs:110-115,247-256, 518-531 and 533 in which the corresponding CDR-H3 sequencecontained therein (e.g. corresponding to amino acid residues H95 to H102by Kabat numbering) is replaced by the CDR-H3 sequence selected from anyone of SEQ ID NOs:7-11, 149-157, 279-287 and 376-378 according to Kabatnumbering or any one of SEQ ID NOs:7-11, 149-157, 279-287 and 376-378according to Chothia numbering or AbM numbering.

In some embodiments, the provided antibody or antigen-binding fragmentthereof comprises a CDR-H3 comprising the amino acid sequence selectedfrom any one of SEQ ID NOs:7-10, 149, 153-157 and 376, according toKabat numbering, Chothia numbering or AbM numbering. In someembodiments, the provided antibody or antigen-binding fragment thereofcomprises a CDR-H3 comprising the amino acid sequence selected from anyone of SEQ ID NOs: 7, 9, 10 and 157, according to Kabat numbering,Chothia numbering or AbM numbering. In some embodiments, the providedantibody or antigen-binding fragment thereof comprises a CDR-H3comprising the amino acid sequence selected from any one of SEQ ID NOs:10 and 157, according to Kabat numbering, Chothia numbering or AbMnumbering.

In some embodiments, the V_(H) region of a provided antibody orantigen-binding fragment thereof comprises a CDR-H3 contained within theV_(H) region amino acid sequence selected from any one of SEQ IDNOs:110-115, 247-256, 518-531 and 533. In some embodiments, the V_(H)region of a provided antibody or antigen-binding fragment thereofcomprises a CDR-H3 contained within the V_(H) region amino acid sequenceof SEQ ID NO:112. In some embodiments, the V_(H) region of a providedantibody or antigen-binding fragment thereof comprises a CDR-H3contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs:110-113, 115, 248, 252-256 and 518-522. In someembodiments, the V_(H) region of a provided antibody or antigen-bindingfragment thereof comprises a CDR-H3 contained within the V_(H) regionamino acid sequence selected from any one of SEQ ID NOs:110, 112, 115,256 and 519. In some embodiments, the V_(H) region of a providedantibody or antigen-binding fragment thereof comprises a CDR-H3contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs:115 and 256.

In some embodiments, the V_(H) region of the antibody or antigen-bindingfragment thereof is one that includes a heavy chain complementarilydetermining region 1 (CDR-H1) comprising the amino acid sequence ofX₁X₂X₃MX₄ (SEQ ID NO:353) Xi is D or S; X₂ is Y or S; X₃ is A, G, W, orY; and X₄ is H, Q, or S. In some embodiments, in said CDR-H1, Xi is D;X₂ is Y; X₃ is Y; and X₄ is S.

In some embodiments, the V_(H) region of a provided antibody orantigen-binding fragment thereof contains a CDR-H1 having the amino acidsequence comprising the amino acid sequence selected from any one of SEQID NOs:1-3 and 140-144 according to Kabat numbering. In someembodiments, the V_(H) region of a provided antibody or antigen-bindingfragment thereof contains a CDR-H1 having the amino acid sequencecomprising the amino acid sequence selected from any one of SEQ IDNOs:12-15 and 158-160 according to Chothia numbering. In someembodiments, the V_(H) region of a provided antibody or antigen-bindingfragment thereof contains a CDR-H1 having the amino acid sequencecomprising the amino acid sequence selected from any one of SEQ IDNOs:19-22, 165-169 and 509 according to AbM numbering. In someembodiments, the V_(H) region of a provided antibody or antigen-bindingfragment thereof contains a CDR-H1 having the amino acid sequence of SEQID NO:2, 13 or 20. In any of such examples, the provided antibody orantigen-binding fragment thereof can contain a V_(H) region sequenceselected from any one of SEQ ID NOs:110-115, 247-256, 518-531 and 533 inwhich the corresponding CDR-H1 sequence contained therein (e.g.corresponding to amino acid residues H31 to H35 by Kabat numbering) isreplaced by the CDR-H1 sequence selected from any one of SEQ ID NOs:1-3and 140-144 according to Kabat numbering, any one of SEQ ID NOs:12-15and 158-160 according to Chothia numbering, or any one of SEQ IDNOs:19-22, 165-169 and 509 according to AbM numbering.

In some embodiments, the V_(H) region of a provided antibody orantigen-binding fragment thereof contains a CDR-H1 having the amino acidsequence comprising the amino acid sequence selected from any one of SEQID NOs:1-3, 141, 143 and 144 according to Kabat numbering, any one ofSEQ ID NOs:12-15, 158 and 160 according to Chothia numbering, or any oneof SEQ ID NOs:19-22, 166, 168 or 169 according to AbM numbering. In someembodiments, the V_(H) region of a provided antibody or antigen-bindingfragment thereof contains a CDR-H1 having the amino acid sequencecomprising the amino acid sequence selected from any one of SEQ ID NOs:1 and 2 according to Kabat numbering, any one of SEQ ID NOs: 12 and 13according to Chothia numbering, or any one of SEQ ID NOs: 19 and 20according to AbM numbering. In some embodiments, the V_(H) region of aprovided antibody or antigen-binding fragment thereof contains a CDR-H1having the amino acid sequence comprising the amino acid sequence of SEQID NO:2 according to Kabat numbering, SEQ ID NO:13 according to Chothianumbering, or SEQ ID NO:20 according to AbM numbering.

In some embodiments, the V_(H) region of a provided antibody orantigen-binding fragment thereof contains a CDR-H1 contained within theV_(H) region amino acid sequence selected from any one of SEQ IDNOs:110-115, 247-256, 518-531 and 533. In some embodiments, the V_(H)region of a provided antibody or antigen-binding fragment thereofcontains a CDR-H1 contained within the V_(H) region amino acid sequenceof SEQ ID NO:112. In some embodiments, the V_(H) region of a providedantibody or antigen-binding fragment thereof comprises a CDR-H1contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs:110-113, 115, 248, 252-256 and 518-522. In someembodiments, the V_(H) region of a provided antibody or antigen-bindingfragment thereof comprises a CDR-H1 contained within the V_(H) regionamino acid sequence selected from any one of SEQ ID NOs:110, 112, 115,256 and 519. In some embodiments, the V_(H) region of a providedantibody or antigen-binding fragment thereof comprises a CDR-H1contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs:115 and 256.

In some embodiments, the V_(H) region of a provided antibody orantigen-binding fragment thereof is one that includes a heavy chaincomplementarity determining region 2 (CDR-H2) comprising the amino acidsequence of X₁IX₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁YX₁₂X₁₃X₁₄X₁₅X₁₆X₁₇ (SEQ IDNO:354), wherein Xi is F, G, H, V, W or Y; X₂ is N, R, S or V; X₃ is P,Q, S, V, W or Y; X₄ is K or null; X₅ is A or null; X₆ is D, G, N, S, orY; X₇ is G or S; X₈ is G or S; X₉ is E, G, N, T or S; X₁₀ is I, K, or T;X₁₁ is E, G, N or Y; X₁₂ is A or V; X₁₃ is A, D or Q; X₁₄ is K or S; X₁₅is F or V; X₁₆ is K or Q; and X₁₇ is E or G. In some embodiments in saidCDR-H2, Xi is Y; X₂ is S, X₃ is 5; X₄ is null; X₅ is null; X₆ is 5; X₇is G; X₈ is S; X₉ is T; X₁₀ is I; X₁₁ is Y; X₁₂ is A; X₁₃ is D; X₁₄ is5; X₁₅ is V; X₁₆ is K; and X₁₇ is G.

In some embodiments, the V_(H) region of a provided antibody orantigen-binding fragment thereof contains a CDR-H2 comprising the aminoacid sequence selected from any one of SEQ ID NOs:4-6, 145-148 and372-374 according to Kabat numbering. In some embodiments, the V_(H)region of a provided antibody or antigen-binding fragment thereofcontains a CDR-H2 comprising the amino acid sequence selected from anyone of SEQ ID NOs:16-18, 161-164 and 514-516 according to Chothianumbering. In some embodiments, the V_(H) region of a provided antibodyor antigen-binding fragment thereof contains a CDR-H2 comprising theamino acid sequence selected from any one of SEQ ID NOs:23-25, 170-173and 510-512 according to AbM numbering. In some embodiments, the V_(H)region of a provided antibody or antigen-binding fragment thereofcontains a CDR-H2 having the amino acid sequence of SEQ ID NO:5according to Kabat numbering. In some embodiments, the V_(H) region of aprovided antibody or antigen-binding fragment thereof contains a CDR-H2having the amino acid sequence of SEQ ID NO:17 according to Chothianumbering. In some embodiments, the V_(H) region of a provided antibodyor antigen-binding fragment thereof contains a CDR-H2 having the aminoacid sequence of SEQ ID NO:24 according to AbM numbering. In any of suchexamples, the provided antibody or antigen-binding fragment thereof cancontain a V_(H) region sequence selected from any one of SEQ IDNOs:110-115, 247-256, 518-531 and 533 in which the corresponding CDR-H2sequence contained therein (e.g. corresponding to amino acid residuesH50 to H65 by Kabat numbering) is replaced by the CDR-H2 sequenceselected from any one of SEQ ID NOs:4-6, 145-148 and 372-374, any one ofSEQ ID NOs:16-18, 161-164 and 514-516 according to Chothia numbering, orany one of SEQ ID NOs:23-25, 170-173 and 510-512 according to AbMnumbering.

In some embodiments, the V_(H) region of a provided antibody orantigen-binding fragment thereof contains a CDR-H2 having the amino acidsequence comprising the amino acid sequence selected from any one of SEQID NOs:4-6, 145, 147, 148 and 372 according to Kabat numbering, any oneof SEQ ID NOs:16-18, 161, 163, 164 and 514 according to Chothianumbering, or any one of SEQ ID NOs:23-25, 170, 172, 173 and 510according to AbM numbering. In some embodiments, the V_(H) region of aprovided antibody or antigen-binding fragment thereof contains a CDR-H2having the amino acid sequence comprising the amino acid sequenceselected from any one of SEQ ID NOs: 4 and 5 according to Kabatnumbering, any one of SEQ ID NOs: 16 and 17 according to Chothianumbering, or any one of SEQ ID NOs: 23 and 24 according to AbMnumbering. In some embodiments, the V_(H) region of a provided antibodyor antigen-binding fragment thereof contains a CDR-H2 having the aminoacid sequence comprising the amino acid sequence of SEQ ID NO:5according to Kabat numbering, SEQ ID NO:17 according to Chothianumbering, or SEQ ID NO:24 according to AbM numbering.

In some embodiments, the V_(H) region of a provided antibody orantigen-binding fragment thereof contains a CDR-H2 contained within theV_(H) region amino acid sequence selected from any one of SEQ IDNOs:110-115, 247-256, 518-531 and 533. In some embodiments, the V_(H)region of a provided antibody or antigen-binding fragment thereofcontains a CDR-H2 contained within the V_(H) region amino acid sequenceof SEQ ID NO:112. In some embodiments, the V_(H) region of a providedantibody or antigen-binding fragment thereof comprises a CDR-H2contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs:110-113, 115, 248, 252-256 and 518-522. In someembodiments, the V_(H) region of a provided antibody or antigen-bindingfragment thereof comprises a CDR-H2 contained within the V_(H) regionamino acid sequence selected from any one of SEQ ID NOs:110, 112, 115,256 and 519. In some embodiments, the V_(H) region of a providedantibody or antigen-binding fragment thereof comprises a CDR-H2contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs:115 and 256.

In some embodiments, the provided antibody or antigen-binding fragmentthereof contains a CDR-H1 that is or comprises the amino acid sequenceselected from any one of SEQ ID NOs:1-3 and 140-144 according to Kabatnumbering; a CDR-H2 that is or comprises the amino acid sequenceselected from any one of SEQ ID NOs:4-6, 145-148 and 372-374 accordingto Kabat numbering; and a CDR-H3 that is or comprises the amino acidsequence selected from any one of SEQ ID NOs:7-11, 149-157, 279-287 and376-378 according to Kabat numbering. In some embodiments, the providedantibody or antigen-binding fragment thereof contains a CDR-H1 that isor comprises the amino acid sequence selected from any one of SEQ IDNOs:12-15 and 158-160 according to Chothia numbering; a CDR-H2 that isor comprises the amino acid sequence selected from any one of SEQ IDNOs:16-18, 161-164 and 514-516 according to Chothia numbering; and aCDR-H3 that is or comprises the amino acid sequence selected from anyone of SEQ ID NOs:7-11, 149-157, 279-287 and 376-378 according toChothia numbering. In some embodiments, the provided antibody orantigen-binding fragment thereof contains a CDR-H1 that is or comprisesthe amino acid sequence selected from any one of SEQ ID NO:19-22,165-169 and 509 according to AbM numbering; a CDR-H2 that is orcomprises the amino acid sequence selected from any one of SEQ IDNOs:23-25, 170-173 and 510-512 according to AbM numbering; and a CDR-H3that is or comprises the amino acid sequence selected from any one ofSEQ ID NOs:7-11, 149-157, 279-287 and 376-378 according to AbMnumbering.

In some embodiments, the V_(H) region of a provided antibody orantigen-binding fragment thereof comprises a CDR-H1, CDR-H2, and/orCDR-H3 according to Kabat numbering as shown in Table 2 and Table 4. Insome embodiments, the V_(H) region of a provided antibody orantigen-binding fragment thereof comprises a CDR-H1, CDR-H2, and/orCDR-H3 according to Chothia numbering as shown in Table 4. In someembodiments, the V_(H) region of a provided antibody or antigen-bindingfragment thereof comprises a CDR-H1, CDR-H2, and/or CDR-H3 according toAbM numbering as shown in Table 4.

In some embodiments, the provided antibody or antigen-binding fragmentthereof comprises an V_(H) region comprising a CDR-H1, CDR-H2, andCDR-H3 selected from the group consisting of: a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOs:1, 4, and 7,respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOs:2, 5, and 8, respectively; a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOs:2, 5, and 9,respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOs:2, 5, and 10, respectively; a CDR-H1, CDR-H2, andCDR-H3 comprising the amino acid sequence of SEQ ID NOs:3, 6, and 11,respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOs:140, 145, and 149, respectively; a CDR-H1,CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:141,145, and 149, respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising theamino acid sequence of SEQ ID NOs:141, 145, and 150, respectively; aCDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ IDNOs:142, 146, and 151, respectively; a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOs:2, 5, and 152,respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOs:143, 147, and 153, respectively; a CDR-H1,CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:144,148, and 154, respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising theamino acid sequence of SEQ ID NOs:3, 6, and 155, respectively; a CDR-H1,CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:2,5, and 156, respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising theamino acid sequence of SEQ ID NOs:2, 5, and 157, respectively; a CDR-H1,CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:2,6, and 376, respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising theamino acid sequence of SEQ ID NOs:3, 372, and 376, respectively; aCDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ IDNOs:3, 6, and 376, respectively; a CDR-H1, CDR-H2, and CDR-H3 comprisingthe amino acid sequence of SEQ ID NOs:3, 6, and 377, respectively; aCDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence of SEQ IDNOs:2, 373, and 152, respectively; a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence of SEQ ID NOs:2, 5, and 378,respectively; a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOs:2, 374, and 9, respectively, according to Kabatnumbering. In some embodiments, the provided antibody or antigen-bindingfragment thereof comprises an V_(H) region comprising a CDR-H1, CDR-H2,and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:2, 5, and 9,respectively, according to Kabat numbering. In some embodiments, theprovided antibody or antigen-binding fragment thereof comprises an V_(H)region comprising a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOs:13, 17, and 9, respectively, according to Chothianumbering. In some embodiments, the provided antibody or antigen-bindingfragment thereof comprises an V_(H) region comprising a CDR-H1, CDR-H2,and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:20, 24, and9, respectively, according to AbM numbering.

For example, the antibody or antigen-binding fragment thereof providedherein comprises an V_(H) region comprising a CDR-H1, CDR-H2, and CDR-H3comprising the amino acid sequence selected from among: SEQ ID NOs:1, 4,and 7; SEQ ID NOs:2, 5, and 8; SEQ ID NOs:2, 5, and 9; SEQ ID NOs:2, 5,and 10; SEQ ID NOs:3, 6, and 11; SEQ ID NOs:140, 145, and 149; SEQ IDNOs:141, 145, and 149; SEQ ID NOs:141, 145, and 150; SEQ ID NOs:142,146, and 151; SEQ ID NOs:2, 5, and 152; SEQ ID NOs:143, 147, and 153;SEQ ID NOs:144, 148, and 154; SEQ ID NOs:3, 6, and 155; SEQ ID NOs:2, 5,and 156; SEQ ID NOs:2, 5, and 157; SEQ ID NOs:2, 6, and 376; SEQ IDNOs:3, 372, and 376; SEQ ID NOs:3, 6, and 376; SEQ ID NOs:3, 6, and 377;SEQ ID NOs:2, 373, and 152; SEQ ID NOs:2, 5, and 378; SEQ ID NOs:2, 374,and 9, respectively, according to Kabat numbering.

In some embodiments, the antibody or antigen-binding fragment thereofprovided herein comprises an V_(H) region comprising a CDR-H1, CDR-H2,and CDR-H3 comprising the amino acid sequence selected from among: SEQID NOs:1, 4, and 7; SEQ ID NOs:2, 5, and 8; SEQ ID NOs:2, 5, and 9; SEQID NOs:2, 5, and 10; SEQ ID NOs:141, 145, and 149; SEQ ID NOs:143, 147,and 153; SEQ ID NOs:144, 148, and 154; SEQ ID NOs:3, 6, and 155; SEQ IDNOs:2, 5, and 156; SEQ ID NOs:2, 5, and 157; SEQ ID NOs:2, 6, and 376;SEQ ID NOs:3, 372, and 376; and SEQ ID NOs:3, 6, and 376, respectively,according to Kabat numbering. In some embodiments, the antibody orantigen-binding fragment thereof provided herein comprises an V_(H)region comprising a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence selected from among: SEQ ID NOs:1, 4, and 7; SEQ ID NOs:2, 5,and 9; SEQ ID NOs:2, 5, and 10; and SEQ ID NOs:2, 5, and 157,respectively, according to Kabat numbering. In some embodiments, theantibody or antigen-binding fragment thereof provided herein comprisesan V_(H) region comprising a CDR-H1, CDR-H2, and CDR-H3 comprising theamino acid sequence selected from among: SEQ ID NOs:2, 5, and 10; andSEQ ID NOs:2, 5, and 157, respectively, according to Kabat numbering.

In some embodiments, the provided antibody or antigen-binding fragmentthereof comprises a CDR-H1, CDR-H2 and CDR-H3, respectively, comprisingthe amino acid sequence of a CDR-H1, a CDR-H2, and a CDR-H3 containedwithin the V_(H) region amino acid sequence selected from any one of SEQID NOs:110-115, 247-256, 518-531 and 533. In some embodiments, theprovided antibody or antigen-binding fragment thereof comprises aCDR-H1, CDR-H2 and CDR-H3, respectively, comprising the amino acidsequence of a CDR-H1, a CDR-H2, and a CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:112. In some embodiments, theV_(H) region of a provided antibody or antigen-binding fragment thereofcomprises a CDR-H1, CDR-H2 and CDR-H3, respectively, comprising theamino acid sequence of a CDR-H1, a CDR-H2, and a CDR-H3 contained withinthe V_(H) region amino acid sequence selected from any one of SEQ IDNOs:110-113, 115, 248, 252-256 and 518-522. In some embodiments, theV_(H) region of a provided antibody or antigen-binding fragment thereofcomprises a CDR-H1, CDR-H2 and CDR-H3, respectively, comprising theamino acid sequence of a CDR-H1, a CDR-H2, and a CDR-H3 contained withinthe V_(H) region amino acid sequence selected from any one of SEQ IDNOs:110, 112, 115, 256 and 519. In some embodiments, the V_(H) region ofa provided antibody or antigen-binding fragment thereof comprises aCDR-H1, CDR-H2 and CDR-H3, respectively, comprising the amino acidsequence of a CDR-H1, a CDR-H2, and a CDR-H3 contained within the V_(H)region amino acid sequence selected from any one of SEQ ID NOs:115 and256.

In some embodiments of the antibody or antigen-binding fragment thereofprovided herein, the V_(H) region comprises any of the CDR-H1, CDR-H2and CDR-H3 as described and comprises a framework region 1 (FR1), a FR2,a FR3 and/or a FR4 having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, or 99% sequence identity, respectively, to a FR1, a FR2, a FR3and/or a FR4 contained within the V_(H) region amino acid sequenceselected from any one of SEQ ID NOs:110-115, 247-256, 518-531 and 533.For example, the anti-BCMA antibody or antigen-binding fragment thereofcan comprise a CDR-H1, CDR-H2 and CDR-H3, respectively, contained withinthe V_(H) region amino acid sequence selected from any one of SEQ IDNOs:110-115, 247-256, 518-531 and 533, and a framework region (e.g., aFR1, a FR2, a FR3 and/or a FR4) that contains at least 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to a frameworkregion (e.g., a FR1, a FR2, a FR3 and/or a FR4) contained within theV_(H) region amino acid sequence selected from any one of SEQ IDNOs:110-115, 247-256, 518-531 and 533. In some embodiments, the V_(H)region comprises a FR1, a FR2, a FR3 and/or a FR4 selected from a FR1comprising the amino acid sequence selected from any one of SEQ IDNOs:59-63, 195-203 and 434-439; a FR2 comprising the amino acid sequenceselected from any one of SEQ ID NOs:64-66 and 204-209; a FR3 comprisingthe amino acid sequence selected from any one of SEQ ID NOs:67-69,210-216, 441 and 443; and/or a FR4 comprising the amino acid sequenceselected from any one of SEQ ID NOs:70-71, 217-220, 444 and 445. In someembodiments, the V_(H) region comprises a FR1 comprising the amino acidsequence of SEQ ID NO:61, a FR2 comprising the amino acid sequence ofSEQ ID NO:65, a FR3 comprising the amino acid sequence of SEQ ID NO:69,and/or a FR4 comprising the amino acid of SEQ ID NO:70.

In some embodiments, the provided antibody or antigen-binding fragmentthereof comprises a V_(H) region comprising the amino acid sequenceselected from any one of SEQ ID NOs:110-115, 247-256, 518-531 and 533.In some embodiments, provided antibody or antigen-binding fragmentthereof comprises a V_(H) region comprising the amino acid sequenceselected from any one of SEQ ID NOs: 110-113, 115, 248, 252-256 and518-522. In some embodiments, provided antibody or antigen-bindingfragment thereof comprises a V_(H) region comprising the amino acidsequence selected from any one of SEQ ID NOs: 110, 112, 115, 256 and519. In some embodiments, provided antibody or antigen-binding fragmentthereof comprises a V_(H) region comprising the amino acid sequenceselected from any one of SEQ ID NOs:115 and 256.

Also provided are antibodies and antigen-binding fragments thereofhaving sequences at least at or about at least 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% identical to such sequences. For example,provided herein is an antibody or antigen-binding fragment comprising aV_(H) region comprising an amino acid sequence having at least 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to a V_(H)region amino acid sequence selected from any one of SEQ ID NOs:110-115,247-256, 518-531 and 533.

In some embodiments, the antibody is a single domain antibody (sdAb)comprising only a V_(H) region sequence or a sufficient antigen-bindingportion thereof, such as any of the above described V_(H) sequences(e.g., a CDR-H1, a CDR-H2, a CDR-H3 and/or a CDR-H4).

In some embodiments, an antibody provided herein (e.g., an anti-BCMAantibody) or antigen-binding fragment thereof comprising a V_(H) regionfurther comprises a light chain or a sufficient antigen binding portionthereof. For example, in some embodiments, the antibody orantigen-binding fragment thereof contains a V_(H) region and a V_(L)region, or a sufficient antigen-binding portion of a V_(H) and V_(L)region. In such embodiments, a V_(H) region sequence can be any of theabove described V_(H) sequence. In some such embodiments, the antibodyis an antigen-binding fragment, such as a Fab or an scFv. In some suchembodiments, the antibody is a full-length antibody that also contains aconstant region.

In some embodiments, the antibody, e.g., antigen-binding fragmentthereof, has a light chain variable (V_(L)) region having the amino acidsequence selected from any one of SEQ ID NOs:116-127, 257-267, 534-550and 552-557, or an amino acid sequence that has at least 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to a V_(L) regionamino acid sequence selected from any one of SEQ ID NOs:116-127,257-267, 534-550 and 552-557.

In some embodiments, the V_(L) region of the antibody described herein(e.g., an anti-BCMA antibody) or antigen-binding fragment thereof is onethat includes a light chain complementarity determining region 3(CDR-L3) comprising the amino acid sequence X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂,(SEQ ID NO:358), wherein Xi is A, C, G, H, I, Q or S; X₂ is A, Q, S orV; X₃ is S, W or Y; X₄ is D, F, G, H or Y; X₅ is D, G, M, R, S or T; X₆is A, G, H, L, R, S, T or Y; X₇ is L, P, R, S or null; X₈ is D, G, N, R,S, T or null; X₉ is A, G, H, L, P or null; X₁₀ is F, S or null; X₁₁ isL, P, W or Y; and X₁₂ is S, T or V. In some embodiments, in said CDR-L3,Xi is H; X₂ is V; X₃ is W; X₄ is D; X₅ is R; X₆ is 5; X₇ is R; X₈ is D;X₉ is H; X₁₀ is null; X₁₁ is Y; and X₁₂ is V.

In some embodiments, the provided antibody or antigen-binding fragmentthereof contains a CDR-L3 comprising the amino acid sequence selectedfrom any one of SEQ ID NOs:47-58, 184-194, 415-427 and 429-433 accordingto Kabat numbering, Chothia numbering or AbM numbering. In someembodiments, the provided antibody or antigen-binding fragment thereofcontains a CDR-L3 having the amino acid sequence of SEQ ID NO:55according to Kabat numbering, Chothia numbering or AbM numbering. In anyof such examples, the provided antibody or antigen-binding fragmentthereof can contain a V_(L) region sequence selected from any one of SEQID NOs:116-127, 257-267, 534-550 and 552-557 in which the correspondingCDR-L3 sequence contained therein (e.g. corresponding to amino acidresidues L89 to L97 by Kabat numbering) is replaced by the CDR-L3sequence selected from any one of SEQ ID NOs:47-58, 184-194, 415-427 and429-433 according to Kabat numbering, Chothia numbering or AbMnumbering.

In some embodiments, the provided antibody or antigen-binding fragmentthereof comprises a CDR-L3 comprising the amino acid sequence selectedfrom any one of SEQ ID NOs:47-49, 51, 52, 55, 56, 185, 189-194, 415-418and 421, according to Kabat numbering, Chothia numbering or AbMnumbering. In some embodiments, the provided antibody or antigen-bindingfragment thereof comprises a CDR-L3 comprising the amino acid sequenceselected from any one of SEQ ID NOs: 47, 51, 55, 194, 416 and 421,according to Kabat numbering, Chothia numbering or AbM numbering. Insome embodiments, the provided antibody or antigen-binding fragmentthereof comprises a CDR-L3 comprising the amino acid sequence selectedfrom any one of SEQ ID NOs: 194 and 421, according to Kabat numbering,Chothia numbering or AbM numbering.

In some embodiments, the V_(L) region of a provided antibody orantigen-binding fragment thereof comprises a CDR-L3 contained within theV_(L) region amino acid sequence selected from any one of SEQ IDNOs:116-127, 257-267, 534-550 and 552-557. In some embodiments, theV_(L) region of a provided antibody or antigen-binding fragment thereofcomprises a CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:124. In some embodiments, the V_(L) region of a providedantibody or antigen-binding fragment thereof comprises a CDR-L3contained within the V_(L) region amino acid sequence selected from anyone of SEQ ID NOs:116-118, 120, 121, 124, 125, 258, 262-267 and 534-538.In some embodiments, the V_(L) region of a provided antibody orantigen-binding fragment thereof comprises a CDR-L3 contained within theV_(L) region amino acid sequence selected from any one of SEQ IDNOs:116, 120, 124, 267, 535 and 536. In some embodiments, the V_(L)region of a provided antibody or antigen-binding fragment thereofcomprises a CDR-L3 contained within the V_(L) region amino acid sequenceselected from any one of SEQ ID NOs:267 and 536.

In some embodiments, the V_(L) region of the antibody described herein(e.g., an anti-BCMA antibody) or antigen-binding fragment thereof is onethat includes a light chain complementarily determining region 1(CDR-L1) that contains the amino acid sequence:X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃X₁₄X₁₅X₁₆X₁₇ (SEQ ID NO:356), wherein Xiis G, K, R, S or T; X₂ is A, G or S; X₃ is G, N, S or T; X₄ is G, K, N,Q, R or S; X₅ is S or null; X₆ is D, N, V or null; X₇ is L, V or null;X₈ is H, S, Y or null; X₉ is S, T or null; X₁₀ is S or null; X₁₁ is D,G, I, N, S or null; X₁₂ is D, E, G, K, I, N or null; X₁₃ is F, G, K, N,R, S, Y or null; X₁₄ is D, K, N, T or null; X₁₅ is A, D, G, L, N, S, Tor Y; X₁₆ is L or V; X₁₇ is A, H, N, Q or S. In some embodiments, Xi isG; X₂ is A; X₃ is N; X₄ is N; X₅ is null; X₆ is null; X₇ is null; X₈ isnull; X₉ is null; X₁₀ is null; X₁₁ is I; X₁₂ is G; X₁₃ is S; X₁₄ is K;X₁₅ is S; X₁₆ is V; X₁₇ is H.

In some embodiments, the provided antibody or antigen-binding fragmentthereof contains a CDR-L1 comprising the amino acid sequence selectedfrom any one of SEQ ID NOs:26-36, 174-178, 380-392 and 394-398 accordingto Kabat numbering, Chothia numbering or AbM numbering. In someembodiments, the provided antibody or antigen-binding fragment thereofcontains a CDR-L1 having the amino acid sequence of SEQ ID NO:33according to Kabat numbering, Chothia numbering or AbM numbering. In anyof such examples, the provided antibody or antigen-binding fragmentthereof can contain a V_(L) region sequence selected from any one of SEQID NOs:116-127, 257-267, 534-550 and 552-557 in which the correspondingCDR-L1 sequence contained therein (e.g. corresponding to amino acidresidues L24 to L34 by Kabat numbering) is replaced by the CDR-L1sequence selected from any one of SEQ ID NOs:26-36, 174-178, 380-392 and394-398 according to Kabat numbering, Chothia numbering or AbMnumbering.

In some embodiments, the V_(L) region of a provided antibody orantigen-binding fragment thereof contains a CDR-L1 having the amino acidsequence comprising the amino acid sequence selected from any one of SEQID NOs:26-28, 30, 31, 33, 34, 174, 176-178 and 380-382, according toKabat numbering, Chothia numbering or AbM numbering. In someembodiments, the V_(L) region of a provided antibody or antigen-bindingfragment thereof contains a CDR-L1 having the amino acid sequencecomprising the amino acid sequence selected from any one of SEQ IDNOs:26, 30, 33, 178 and 380, according to Kabat numbering, Chothianumbering or AbM numbering. In some embodiments, the V_(L) region of aprovided antibody or antigen-binding fragment thereof contains a CDR-L1having the amino acid sequence comprising the amino acid sequenceselected from any one of SEQ ID NOs:33 and 178, according to Kabatnumbering, Chothia numbering or AbM numbering.

In some embodiments, the V_(L) region of a provided antibody orantigen-binding fragment thereof comprises a CDR-L1 contained within theV_(L) region amino acid sequence selected from any one of SEQ IDNOs:116-127, 257-267, 534-550 and 552-557. In some embodiments, theV_(L) region of a provided antibody or antigen-binding fragment thereofcomprises a CDR-L1 contained within the V_(L) region amino acid sequenceof SEQ ID NO:124. In some embodiments, the V_(L) region of a providedantibody or antigen-binding fragment thereof comprises a CDR-L1contained within the V_(L) region amino acid sequence selected from anyone of SEQ ID NOs:116-118, 120, 121, 124, 125, 258, 262-267 and 534-538,according to Kabat numbering, Chothia numbering or AbM numbering. Insome embodiments, the V_(L) region of a provided antibody orantigen-binding fragment thereof comprises a CDR-L1 contained within theV_(L) region amino acid sequence selected from any one of SEQ IDNOs:116, 120, 124, 267, 535 and 536, according to Kabat numbering,Chothia numbering or AbM numbering. In some embodiments, the V_(L)region of a provided antibody or antigen-binding fragment thereofcomprises a CDR-L1 contained within the V_(L) region amino acid sequenceselected from any one of SEQ ID NOs:267 and 536, according to Kabatnumbering, Chothia numbering or AbM numbering.

In some embodiments, the V_(L) region of the antibody provided herein(e.g., an anti-BCMA antibody) or antigen-binding fragment thereof is onethat includes a light chain complementarily determining region 2(CDR-L2) that contains the amino acid sequence of X₁X₂X₃X₄X₅X₆X₇ (SEQ IDNO:357), wherein Xi is A, D, E, N, S, V or W; X₂ is A, D, N, S or V; X₃is A, D, H, I, N or S; X₄ is D, K, N, Q, R or T; X₅ is L, R or V; X₆ isA, E, P or Q; and X₇ is A, D, S or T. In some embodiments, Xi is D; X₂is D; X₃ is D; X₄ is D; X₅ is R; X₆ is P; and X₇ is S.

In some embodiments, the provided antibody or antigen-binding fragmentthereof contains a CDR-L2 comprising the amino acid sequence selectedfrom any one of SEQ ID NOs:37-46, 179-183, 399-409 and 411-414 accordingto Kabat numbering, Chothia numbering or AbM numbering. In someembodiments, the provided antibody or antigen-binding fragment thereofcontains a CDR-L2 having the amino acid sequence of SEQ ID NO:43according to Kabat numbering, Chothia numbering or AbM numbering. In anyof such examples, the provided antibody or antigen-binding fragmentthereof can contain a V_(L) region sequence selected from any one of SEQID NOs:116-127, 257-267, 534-550 and 552-557 in which the correspondingCDR-L2 sequence contained therein (e.g. corresponding to amino acidresidues L50 to L56 by Kabat numbering) is replaced by the CDR-L2sequence selected from any one of SEQ ID NOs:37-46, 179-183, 399-409 and411-414 according to Kabat numbering, Chothia numbering or AbMnumbering.

In some embodiments, the V_(L) region of a provided antibody orantigen-binding fragment thereof comprises a CDR-L2 contained within theV_(L) region amino acid sequence selected from any one of SEQ IDNOs:37-39, 41, 43, 44, 179, 181-183 and 399-401, according to Kabatnumbering, Chothia numbering or AbM numbering. In some embodiments, theV_(L) region of a provided antibody or antigen-binding fragment thereofcomprises a CDR-L2 contained within the V_(L) region amino acid sequenceselected from any one of SEQ ID NOs:37, 39, 43, 183 and 400, accordingto Kabat numbering, Chothia numbering or AbM numbering. In someembodiments, the V_(L) region of a provided antibody or antigen-bindingfragment thereof comprises a CDR-L2 contained within the V_(L) regionamino acid sequence selected from any one of SEQ ID NOs:43 and 183,according to Kabat numbering, Chothia numbering or AbM numbering.

In some embodiments, the V_(L) region of a provided antibody orantigen-binding fragment thereof comprises a CDR-L2 contained within theV_(L) region amino acid sequence selected from any one of SEQ IDNOs:116-127, 257-267, 534-550 and 552-557. In some embodiments, theV_(L) region of a provided antibody or antigen-binding fragment thereofcomprises a CDR-L2 contained within the V_(L) region amino acid sequenceof SEQ ID NO:124. In some embodiments, the V_(L) region of a providedantibody or antigen-binding fragment thereof comprises a CDR-L2contained within the V_(L) region amino acid sequence selected from anyone of SEQ ID NOs:116-118, 120, 121, 124, 125, 258, 262-267 and 534-538.In some embodiments, the V_(L) region of a provided antibody orantigen-binding fragment thereof comprises a CDR-L2 contained within theV_(L) region amino acid sequence selected from any one of SEQ IDNOs:116, 120, 124, 267, 535 and 536. In some embodiments, the V_(L)region of a provided antibody or antigen-binding fragment thereofcomprises a CDR-L2 contained within the V_(L) region amino acid sequenceselected from any one of SEQ ID NOs:267 and 536.

In some embodiments, the provided antibody or antigen-binding fragmentthereof contains a CDR-L1 that is or comprises the amino acid sequenceselected from any one of SEQ ID NOs:26-36, 174-178, 380-392 and 394-398according to Kabat numbering, Chothia numbering or AbM numbering; aCDR-L2 that is or comprises the amino acid sequence selected from anyone of SEQ ID NOs:37-46, 179-183, 399-409 and 411-414 according to Kabatnumbering, Chothia numbering or AbM numbering; and a CDR-L3 that is orcomprises the amino acid sequence selected from any one of SEQ IDNOs:47-58, 184-194, 415-427 and 429-433 according to Kabat numbering,Chothia numbering or AbM numbering.

In some embodiments, the V_(L) region of a provided antibody orantigen-binding fragment thereof comprises a CDR-L1, CDR-L2, and/orCDR-L3 according to Kabat numbering as shown in Table 2 and Table 4. Insome embodiments, the V_(L) region of a provided antibody orantigen-binding fragment thereof comprises a CDR-L1, CDR-L2, and/orCDR-L3 according to Chothia numbering as shown in Table 4. In someembodiments, the V_(L) region of a provided antibody or antigen-bindingfragment thereof comprises a CDR-L1, CDR-L2, and/or CDR-L3 according toAbM numbering as shown in Table 4.

In some embodiments of the antibody or antigen-binding fragment thereofprovided herein, the V_(L) region comprises a CDR-L1, a CDR-L2, and aCDR-L3 selected from among: a CDR-L1, CDR-L2, and CDR-L3 comprising theamino acid sequence of SEQ ID NOs:26, 37, and 47, respectively; aCDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ IDNOs:27, 38, and 48, respectively; a CDR-L1, CDR-L2, and CDR-L3comprising the amino acid sequence of SEQ ID NOs:28, 39, and 49,respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:29, 40, and 50, respectively; a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:30, 39, and51, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:31, 41, and 52, respectively; a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:32, 42, and53, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:30, 39, and 54, respectively; a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:33, 43, and55, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:34, 44, and 56, respectively; a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:35, 45, and57, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:36, 46, and 58, respectively; a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:174, 179,and 184, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the aminoacid sequence of SEQ ID NOs:174, 179, and 185, respectively; a CDR-L1,CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:174,179, and 186, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising theamino acid sequence of SEQ ID NOs:174, 179, and 187, respectively; aCDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ IDNOs:175, 180, and 188, respectively; a CDR-L1, CDR-L2, and CDR-L3comprising the amino acid sequence of SEQ ID NOs:174, 179, and 189,respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:176, 181, and 190, respectively; a CDR-L1,CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:177,182, and 191, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising theamino acid sequence of SEQ ID NOs:174, 179, and 192, respectively; aCDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ IDNOs:178, 183, and 193, respectively; a CDR-L1, CDR-L2, and CDR-L3comprising the amino acid sequence of SEQ ID NOs:178, 183, and 194,respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:30, 399, and 415, respectively; a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:380, 400,and 416, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the aminoacid sequence of SEQ ID NOs:33, 43, and 421, respectively; a CDR-L1,CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:381,401, and 417, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising theamino acid sequence of SEQ ID NOs:382, 402, and 418, respectively; aCDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ IDNOs:383, 403, and 419, respectively; a CDR-L1, CDR-L2, and CDR-L3comprising the amino acid sequence of SEQ ID NOs:384, 39, and 54,respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:385, 180, and 58, respectively; a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:175, 180,and 188, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the aminoacid sequence of SEQ ID NOs:386, 404, and 420, respectively; a CDR-L1,CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:387,405, and 422, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising theamino acid sequence of SEQ ID NOs:388, 406, and 423, respectively; aCDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ IDNOs:388, 407, and 424, respectively; a CDR-L1, CDR-L2, and CDR-L3comprising the amino acid sequence of SEQ ID NOs:389, 408, and 425,respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:390, 183, and 193, respectively; a CDR-L1,CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:391,409, and 426, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising theamino acid sequence of SEQ ID NOs:392, 40, and 427, respectively; aCDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ IDNOs:394, 39, and 429, respectively; a CDR-L1, CDR-L2, and CDR-L3comprising the amino acid sequence of SEQ ID NOs:395, 411, and 430,respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:396, 412, and 431, respectively; a CDR-L1,CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID NOs:396,412, and 58, respectively; a CDR-L1, CDR-L2, and CDR-L3 comprising theamino acid sequence of SEQ ID NOs:397, 413, and 432, respectively; aCDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ IDNOs:398, 414, and 433, respectively. In some embodiments of the antibodyor antigen-binding fragment thereof provided herein, the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOs:33, 43, and 55.

For example, the antibody or antigen-binding fragment thereof providedherein comprises an V_(L) region comprising a CDR-L1, CDR-L2, and CDR-L3comprising the amino acid sequence selected from among: SEQ ID NOs:26,37, and 47; SEQ ID NOs:27, 38, and 48; SEQ ID NOs:28, 39, and 49; SEQ IDNOs:29, 40, and 50; SEQ ID NOs:30, 39, and 51; SEQ ID NOs:31, 41, and52; SEQ ID NOs:32, 42, and 53; SEQ ID NOs:30, 39, and 54; SEQ ID NOs:33,43, and 55; SEQ ID NOs:34, 44, and 56; SEQ ID NOs:35, 45, and 57; SEQ IDNOs:36, 46, and 58; SEQ ID NOs:174, 179, and 184; SEQ ID NOs:174, 179,and 185; SEQ ID NOs:174, 179, and 186; SEQ ID NOs:174, 179, and 187; SEQID NOs:175, 180, and 188; SEQ ID NOs:174, 179, and 189; SEQ ID NOs:176,181, and 190; SEQ ID NOs:177, 182, and 191; SEQ ID NOs:174, 179, and192; SEQ ID NOs:178, 183, and 193; SEQ ID NOs:178, 183, and 194; SEQ IDNOs:30, 399, and 415; SEQ ID NOs:380, 400, and 416; SEQ ID NOs:33, 43,and 421; SEQ ID NOs:381, 401, and 417; SEQ ID NOs:382, 402, and 418; SEQID NOs:383, 403, and 419; SEQ ID NOs:384, 39, and 54; SEQ ID NOs:385,180, and 58; SEQ ID NOs:175, 180, and 188; SEQ ID NOs:386, 404, and 420;SEQ ID NOs:387, 405, and 422; SEQ ID NOs:388, 406, and 423; SEQ IDNOs:388, 407, and 424; SEQ ID NOs:389, 408, and 425; SEQ ID NOs:390,183, and 193; SEQ ID NOs:391, 409, and 426; SEQ ID NOs:392, 40, and 427;SEQ ID NOs:394, 39, and 429; SEQ ID NOs:395, 411, and 430; SEQ IDNOs:396, 412, and 431; SEQ ID NOs:396, 412, and 58; SEQ ID NOs:397, 413,and 432; SEQ ID NOs:398, 414, and 433, respectively.

In some embodiments, the antibody or antigen-binding fragment thereofprovided herein comprises an V_(L) region comprising a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence selected from among: SEQID NOs:26, 37, and 47; SEQ ID NOs:27, 38, and 48; SEQ ID NOs:28, 39, and49; SEQ ID NOs:30, 39, and 51; SEQ ID NOs:31, 41, and 52; SEQ ID NOs:33,43, and 55; SEQ ID NOs:34, 44, and 56; SEQ ID NOs:174, 179, and 185; SEQID NOs:174, 179, and 189; SEQ ID NOs:176, 181, and 190; SEQ ID NOs:177,182, and 191; SEQ ID NOs:174, 179, and 192; SEQ ID NOs:178, 183, and193; SEQ ID NOs:178, 183, and 194; SEQ ID NOs:30, 399, and 415; SEQ IDNOs:380, 400, and 416; SEQ ID NOs:33, 43, and 421; SEQ ID NOs:381, 401,and 417; and SEQ ID NOs:382, 402, and 418, respectively, according toKabat numbering, Chothia numbering or AbM numbering.

In some embodiments, the antibody or antigen-binding fragment thereofprovided herein comprises an V_(L) region comprising a CDR-L1, CDR-L2,and CDR-L3 comprising the amino acid sequence selected from among: SEQID NOs:26, 37, and 47; SEQ ID NOs:30, 39, and 51; SEQ ID NOs:33, 43, and55; SEQ ID NOs:178, 183, and 194; SEQ ID NOs:380, 400, and 416; and SEQID NOs:33, 43, and 421, respectively, according to Kabat numbering,Chothia numbering or AbM numbering. In some embodiments, the antibody orantigen-binding fragment thereof provided herein comprises an V_(L)region comprising a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence selected from among: SEQ ID NOs:178, 183, and 194; and SEQ IDNOs:33, 43, and 421, respectively, according to Kabat numbering, Chothianumbering or AbM numbering.

In some embodiments, the provided antibody or antigen-binding fragmentthereof contains a CDR-L1, CDR-L2, and CDR-L3, respectively, containedwithin the V_(L) region amino acid sequence selected from any one of SEQID NOs:116-127, 257-267, 534-550 and 552-557. In some embodiments, theprovided antibody contains a CDR-L1, CDR-L2, and CDR-L3, respectively,contained within the V_(L) region amino acid sequence selected of SEQ IDNO:124. In some embodiments, the V_(L) region of a provided antibody orantigen-binding fragment thereof comprises a CDR-L1, CDR-L2, and CDR-L3,respectively, contained within the V_(L) region amino acid sequenceselected from any one of SEQ ID NOs:116-118, 120, 121, 124, 125, 258,262-267 and 534-538. In some embodiments, the V_(L) region of a providedantibody or antigen-binding fragment thereof comprises a CDR-L1, CDR-L2,and CDR-L3, respectively, contained within the V_(L) region amino acidsequence selected from any one of SEQ ID NOs:116, 120, 124, 267, 535 and536. In some embodiments, the V_(L) region of a provided antibody orantigen-binding fragment thereof comprises a CDR-L1, CDR-L2, and CDR-L3,respectively, contained within the V_(L) region amino acid sequenceselected from any one of SEQ ID NOs:267 and 536.

In some embodiments of the antibody or antigen-binding fragment thereofprovided herein, the V_(L) region comprises any of the CDR-L1, CDR-L2and CDR-L3 as described and comprises a framework region 1 (FR1), a FR2,a FR3 and/or a FR4 having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, or 99% sequence identity, respectively, to a FR1, a FR2, a FR3and/or a FR4 contained within the V_(L) region amino acid sequenceselected from any one of SEQ ID NOs:116-127, 257-267, 534-550 and552-557. For example, the anti-BCMA antibody or antigen-binding fragmentthereof can comprise a CDR-L1, CDR-L2 and CDR-L3, respectively,contained within the V_(L) region amino acid sequence selected from anyone of SEQ ID NOs:116-127, 257-267, 534-550 and 552-557, and a frameworkregion (e.g., a FR1, a FR2, a FR3 and/or a FR4) that contains at least90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity to aframework region (e.g., a FR1, a FR2, a FR3 and/or a FR4) containedwithin the V_(L) region amino acid sequence selected from any one of SEQID NOs:116-127, 257-267, 534-550 and 552-557. In some embodiments, theV_(L) region comprises a FR1, a FR2, a FR3 and/or a FR4 selected from aFR1 comprising the amino acid sequence selected from any one of SEQ IDNOs:72-82, 221-227, 446-459 and 461-466; a FR2 comprising the amino acidsequence selected from any one of SEQ ID NOs:83-92, 228-232, 467-477 and479-482; a FR3 comprising the amino acid sequence selected from any oneof SEQ ID NOs:93-101, 233-242, 483-495 and 497-501; and/or a FR4comprising the amino acid sequence selected from any one of SEQ IDNOs:102-109, 243-246,502-506 and 508. In some embodiments, the V_(L)region comprises a FR1 comprising the amino acid sequence of SEQ IDNO:79, a FR2 comprising the amino acid sequence of SEQ ID NO:89, a FR3comprising the amino acid sequence of SEQ ID NO:98, and/or a FR4comprising the amino acid sequence of SEQ ID NO:108.

In some embodiments, the provided antibody or antigen-binding fragmentthereof comprises a V_(L) region comprising an amino acid sequenceselected from any one of SEQ ID NOs:116-127, 257-267, 534-550 and552-557. In some embodiments, the provided antibody or antigen-bindingfragment thereof contains a V_(L) region comprises the amino acidsequence of SEQ ID NO:124. In some embodiments, the provided antibody orantigen-binding fragment thereof comprises a V_(L) region comprising anamino acid sequence selected from any one of SEQ ID NOs:116-118, 120,121, 124, 125, 258, 262-267 and 534-538. In some embodiments, theprovided antibody or antigen-binding fragment thereof comprises a V_(L)region comprising an amino acid sequence selected from any one of SEQ IDNOs:116, 120, 124, 267, 535 and 536. In some embodiments, the providedantibody or antigen-binding fragment thereof comprises a V_(L) regioncomprising an amino acid sequence selected from any one of SEQ IDNOs:267 and 536.

Also provided are antibodies having sequences at least at or about atleast 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical tosuch sequences.

In some embodiments, the V_(H) region of the antibody or fragmentcomprises the amino acid sequence selected from any one of SEQ IDNOs:110-115, 247-256, 518-531 and 533 and the V_(L) region of theantibody or fragment comprises the amino acid sequence selected from anyone of SEQ ID NOs:116-127, 257-267, 534-550 and 552-557. In someembodiments, the V_(H) region of the antibody or fragment comprises theamino acid sequence selected from any one of SEQ ID NOs: 110-113, 115,248, 252-256 and 518-522 and the V_(L) region of the antibody orfragment comprises the amino acid sequence selected from any one of SEQID NOs: 116-118, 120, 121, 124, 125, 258, 262-267 and 534-538. In someembodiments, the V_(H) region of the antibody or fragment comprises theamino acid sequence selected from any one of SEQ ID NOs: 110, 112, 115,256 and 519 and the V_(L) region of the antibody or fragment comprisesthe amino acid sequence selected from any one of SEQ ID NOs: 116, 120,124, 267, 535 and 536. In some embodiments, the V_(H) region of theantibody or fragment comprises the amino acid sequence selected from anyone of SEQ ID NOs: 115 and 256 and the V_(L) region of the antibody orfragment comprises the amino acid sequence selected from any one of SEQID NOs: 267 and 536.

Also provided are antibodies and antigen-binding fragments thereofhaving sequences at least at or about at least 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% identical to such sequences. For example,provided herein is an antibody or antigen-binding fragment containing aV_(L) region comprising an amino acid sequence having at least 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to a V_(L)region amino acid sequence selected from any one of SEQ ID NOs:116-127,257-267, 534-550 and 552-557 and/or comprising an amino acid sequencehaving at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%sequence identity to a V_(H) region amino acid sequence selected fromany one of SEQ ID NOs:110-115, 247-256, 518-531 and 533. In someembodiments, the antibody or antigen-binding fragment contains a V_(L)region comprising the amino acid sequence selected from any one of SEQID NOs:116-127, 257-267, 534-550 and 552-557 and a V_(H) region theamino acid sequence selected from any one of SEQ ID NOs:110-115,247-256, 518-531 and 533.

In some embodiments, the V_(H) region of the antibody or antigen-bindingfragment thereof comprises a CDR-H1, a CDR-H2, a CDR-H3, respectively,comprising the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs:110-115, 247-256, 518-531 and 533; and the V_(L)region of the antibody or antigen-binding fragment thereof comprises aCDR-L1, a CDR-L2, a CDR-L3, respectively, comprising the amino acidsequences of CDR-L1, CDR-L2, and CDR-L3, respectively contained withinthe V_(L) region amino acid sequence selected from any one of SEQ IDNOs:116-127, 257-267, 534-550 and 552-557.

In some embodiments, the V_(H) region of the antibody or fragmentcomprises a CDR-H1, a CDR-H2, a CDR-H3, respectively, comprising theamino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within theV_(H) region amino acid sequence selected from any one of SEQ IDNOs:110-115, 247-256, 518-531 and 533 and the V_(L) region of theantibody or fragment comprises a CDR-L1, a CDR-L2, a CDR-L3,respectively, comprising the amino acid sequences of CDR-L1, CDR-L2, andCDR-L3, respectively contained within the V_(L) region amino acidsequence selected from any one of SEQ ID NOs:116-127, 257-267, 534-550and 552-557. In some embodiments, the V_(H) region of the antibody orfragment comprises a CDR-H1, a CDR-H2, a CDR-H3, respectively,comprising the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs:110-113, 115, 248, 252-256 and 518-522 and the V_(L)region of the antibody or fragment comprises a CDR-L1, a CDR-L2, aCDR-L3, respectively, comprising the amino acid sequences of CDR-L1,CDR-L2, and CDR-L3, respectively contained within the V_(L) region aminoacid sequence selected from any one of SEQ ID NOs:116-118, 120, 121,124, 125, 258, 262-267 and 534-538. In some embodiments, the V_(H)region of the antibody or fragment comprises a CDR-H1, a CDR-H2, aCDR-H3, respectively, comprising the amino acid sequences of CDR-H1,CDR-H2, and CDR-H3 contained within the V_(H) region amino acid sequenceselected from any one of SEQ ID NOs:110, 112, 115, 256 and 519 and theV_(L) region of the antibody or fragment comprises a CDR-L1, a CDR-L2, aCDR-L3, respectively, comprising the amino acid sequences of CDR-L1,CDR-L2, and CDR-L3, respectively contained within the V_(L) region aminoacid sequence selected from any one of SEQ ID NOs: 116, 120, 124, 267,535 and 536. In some embodiments, the V_(H) region of the antibody orfragment comprises a CDR-H1, a CDR-H2, a CDR-H3, respectively,comprising the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs: 115 and 256 and the V_(L) region of the antibody orfragment comprises a CDR-L1, a CDR-L2, a CDR-L3, respectively,comprising the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3,respectively contained within the V_(L) region amino acid sequenceselected from any one of SEQ ID NOs:267 and 536.

In some embodiments, the antibody or antigen-binding fragment comprisesa V_(H) having at least 90% sequence identity to the V_(H) sequenceselected from any of SEQ ID NOs:110-115, 247-256, 518-531 and 533; and aV_(L) having at least 90% sequence identity to the V_(L) sequenceselected from any of SEQ ID NOs:116-127, 257-267, 534-550 and 552-557.

In some embodiments, the antibody or antigen-binding fragment comprisesa V_(H) having at least 90% sequence identity to the V_(H) sequenceselected from any of SEQ ID NOs:110, 256 and 519; and a V_(L) having atleast 90% sequence identity to the V_(L) sequence selected from any ofSEQ ID NOs:47, 51, 194 and 416. In some embodiments, said antibody orantigen-binding fragment comprises a V_(H) having at least 90% sequenceidentity to the V_(H) sequence of SEQ ID NO:115; and a V_(L) having atleast 90% sequence identity to the V_(L) sequence of SEQ ID NO:536.

In some embodiments, the antibody or antigen-binding fragment thereofcomprises a V_(H) comprising a CDR-H1, CDR-H2, and CDR-H3, wherein: theCDR-H1 comprises the sequence selected from any of SEQ ID NOs:1-3 and140-144; the CDR-H2 comprises the sequence selected from any of SEQ IDNOs:4-6, 145-148 and 372-374; and the CDR-H3 comprises the sequenceselected from any of SEQ ID NOs:7-11, 149-157, 279-287 and 376-378; anda V_(L) comprising a CDR-L1, CDR-L2, and CDR-L3, wherein: the CDR-L1comprises the sequence selected from any of SEQ ID NOs:26-36, 174-178,380-392 and 394-398; the CDR-L2 comprises the sequence selected from anyof SEQ ID NOs:37-46, 179-183, 399-409 and 411-414; and the CDR-L3comprises the sequence selected from any of SEQ ID NOs:47-58, 184-194,415-427 and 429-433.

In some embodiments, the CDR-H1 comprises the sequence selected from anyof SEQ ID NOs:1 and 2; the CDR-H2 comprises the sequence selected fromany of SEQ ID NOs:4 and 5; and the CDR-H3 comprises the sequenceselected from any of SEQ ID NOs:7 and 157; and the CDR-L1 comprises thesequence selected from any of SEQ ID NOs:26, 30, 178 and 380; the CDR-L2comprises the sequence selected from any of SEQ ID NOs:37, 39, 183 or400; and the CDR-L3 comprises the sequence selected from any of SEQ IDNOs:47, 51, 194 and 416. In some embodiments, the CDR-H1 comprises thesequence of SEQ ID NO:2; the CDR-H2 comprises the sequence of SEQ IDNO:5; and the CDR-H3 comprises the sequence of SEQ ID NO:10; and theCDR-L1 comprises the sequence of SEQ ID NO:33; the CDR-L2 comprises thesequence of SEQ ID NO:43; and the CDR-L3 comprises the sequence of SEQID NO:421.

In some embodiments, the antibody or antigen-binding fragment thereofcomprises a V_(H) and a V_(L), wherein: the V_(H) comprises a CDR-H1,CDR-H2, and CDR-H3 comprising SEQ ID NOS:1, 4, and 7, respectively, andthe V_(L) comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ IDNOS:26, 37, and 47, respectively; the V_(H) comprises a CDR-H1, CDR-H2,and CDR-H3 comprising SEQ ID NOS:2, 5, and 8, respectively, and theV_(L) comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:27,38, and 48, respectively; the V_(H) comprises a CDR-H1, CDR-H2, andCDR-H3 comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:28, 39, and49, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:29, 40, and 50,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:30, 39, and 51,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:31, 41, and 52,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:32, 42, and 53,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:30, 39, and 54,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 9, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:33, 43, and 55,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 10, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:34, 44, and56, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:3, 6, and 11, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:35, 45, and57, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 10, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:36, 46, and58, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:140, 145, and 149, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:174, 179,and 184, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:141, 145, and 149, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:174, 179,and 185, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:141, 145, and 150, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:174, 179,and 186, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:142, 146, and 151, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:174, 179,and 187, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 152, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:175, 180,and 188, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:143, 147, and 153, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:174, 179,and 189, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:144, 148, and 154, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:176, 181,and 190, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:3, 6, and 155, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:177, 182,and 191, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 156, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:174, 179,and 192, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 157, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:178, 183,and 193, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 157, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:178, 183,and 194, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 6, and 376, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:30, 399,and 415, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:380, 400, and 416,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 10, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:33, 43, and421, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:3, 6, and 155, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:177, 182,and 191, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:3, 372, and 376, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:381, 401,and 417, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:3, 6, and 376, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:382, 402,and 418, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:3, 6, and 377, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:383, 403,and 419, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:384, 39, and 54,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 10, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:385, 180,and 58, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 373, and 152, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:175, 180,and 188, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:3, 6, and 11, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:386, 404,and 420, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 378, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:33, 43, and421, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 9, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:387, 405, and 422,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 9, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:388, 406, and 423,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 9, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:388, 407, and 424,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:3, 6, and 376, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:389, 408,and 425, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 157, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:390, 183,and 193, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 374, and 9, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:391, 409,and 426, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:392, 40, and 427,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:394, 39, and 429,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:395, 411, and 430,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:28, 39, and 49,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 10, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:396, 412,and 431, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 10, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:396, 412,and 58, respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 10, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:397, 413,and 432, respectively; or the V_(H) comprises a CDR-H1, CDR-H2, andCDR-H3 comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:398, 414,and 433, respectively.

In some embodiments, the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:26, 37, and 47,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) comprisesa CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:30, 39, and 51,respectively; the V_(H) comprises a CDR-H1, CDR-H2, and CDR-H3comprising SEQ ID NOS:2, 5, and 157, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:178, 183,and 194, respectively; or the V_(H) comprises a CDR-H1, CDR-H2, andCDR-H3 comprising SEQ ID NOS:1, 4, and 7, respectively, and the V_(L)comprises a CDR-L1, CDR-L2, and CDR-L3 comprising SEQ ID NOS:380, 400,and 416, respectively. In some embodiments, the V_(H) comprises aCDR-H1, CDR-H2, and CDR-H3 comprising SEQ ID NOS:2, 5, and 10,respectively, and the V_(L) comprises a CDR-L1, CDR-L2, and CDR-L3comprising SEQ ID NOS:33, 43, and 421, respectively.

In some embodiments, the antibody or antigen-binding fragment thereofcomprises a CDR-H1, CDR-H2, and CDR-H3, respectively, comprising thesequences of CDR-H1, CDR-H2, and CDR-H3 within the V_(H) sequenceselected from any of SEQ ID NOs:110-115, 247-256, 518-531 and 533;and/or a CDR-L1, CDR-L2, and CDR-L3, respectively, comprising thesequences of CDR-L1, CDR-L2, and CDR-L3 within the V_(L) sequenceselected from any of SEQ ID NOs:116-127, 257-267, 534-550 and 552-557.

In some embodiments, the CDR-H1, CDR-H2, and CDR-H3, respectively,comprise the sequences of CDR-H1, CDR-H2, and CDR-H3 within the V_(H)sequence selected from any of SEQ ID NOs:110, 256 and 519; and a CDR-L1,CDR-L2, and CDR-L3, respectively, comprising the sequences of CDR-L1,CDR-L2, and CDR-L3 within the V_(L) sequence selected from any of SEQ IDNOs:116, 120, 267 and 535.

In some embodiments, the CDR-H1, CDR-H2, and CDR-H3, respectively,comprise the sequences of CDR-H1, CDR-H2, and CDR-H3 within SEQ IDNO:115; and a CDR-L1, CDR-L2, and CDR-L3, respectively, comprising thesequences of CDR-L1, CDR-L2, and CDR-L3 within SEQ ID NO:536.

In some embodiments, the antibody or antigen-binding fragment thereofcomprises a V_(H) and a V_(L), wherein: the V_(H) is or comprises aCDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:110, and the V_(L) is orcomprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:116; the V_(H) isor comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:111, and theV_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:117;the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ IDNO:110, and the V_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 withinSEQ ID NO:118; the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3within SEQ ID NO:110, and the V_(L) is or comprises a CDR-L1, CDR-L2 andCDR-L3 within SEQ ID NO:119; the V_(H) is or comprises a CDR-H1, CDR-H2and CDR-H3 within SEQ ID NO:110, and the V_(L) is or comprises a CDR-L1,CDR-L2 and CDR-L3 within SEQ ID NO:120; the V_(H) is or comprises aCDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:110, and the V_(L) is orcomprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:121; the V_(H) isor comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:110, and theV_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:122;the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ IDNO:110, and the V_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 withinSEQ ID NO:123; the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3within SEQ ID NO:112, and the V_(L) is or comprises a CDR-L1, CDR-L2 andCDR-L3 within SEQ ID NO:124; the V_(H) is or comprises a CDR-H1, CDR-H2and CDR-H3 within SEQ ID NO:113, and the V_(L) is or comprises a CDR-L1,CDR-L2 and CDR-L3 within SEQ ID NO:125; the V_(H) is or comprises aCDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:114, and the V_(L) is orcomprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:126; the V_(H) isor comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:115, and theV_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:127;the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ IDNO:247, and the V_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 withinSEQ ID NO:257; the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3within SEQ ID NO:248, and the V_(L) is or comprises a CDR-L1, CDR-L2 andCDR-L3 within SEQ ID NO:258; the V_(H) is or comprises a CDR-H1, CDR-H2and CDR-H3 within SEQ ID NO:249, and the V_(L) is or comprises a CDR-L1,CDR-L2 and CDR-L3 within SEQ ID NO:259; the V_(H) is or comprises aCDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:250, and the V_(L) is orcomprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:260; the V_(H) isor comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:251, and theV_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:261;the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ IDNO:252, and the V_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 withinSEQ ID NO:262; the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3within SEQ ID NO:253, and the V_(L) is or comprises a CDR-L1, CDR-L2 andCDR-L3 within SEQ ID NO:263; the V_(H) is or comprises a CDR-H1, CDR-H2and CDR-H3 within SEQ ID NO:254, and the V_(L) is or comprises a CDR-L1,CDR-L2 and CDR-L3 within SEQ ID NO:264; the V_(H) is or comprises aCDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:255, and the V_(L) is orcomprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:265; the V_(H) isor comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:256, and theV_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:266;the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ IDNO:256, and the V_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 withinSEQ ID NO:267; the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3within SEQ ID NO:518, and the V_(L) is or comprises a CDR-L1, CDR-L2 andCDR-L3 within SEQ ID NO:534; the V_(H) is or comprises a CDR-H1, CDR-H2and CDR-H3 within SEQ ID NO:519, and the V_(L) is or comprises a CDR-L1,CDR-L2 and CDR-L3 within SEQ ID NO:535; the V_(H) is or comprises aCDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:115, and the V_(L) is orcomprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:536; the V_(H) isor comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:520, and theV_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:264;the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ IDNO:521, and the V_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 withinSEQ ID NO:537; the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3within SEQ ID NO:522, and the V_(L) is or comprises a CDR-L1, CDR-L2 andCDR-L3 within SEQ ID NO:538; the V_(H) is or comprises a CDR-H1, CDR-H2and CDR-H3 within SEQ ID NO:523, and the V_(L) is or comprises a CDR-L1,CDR-L2 and CDR-L3 within SEQ ID NO:539; the V_(H) is or comprises aCDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:519, and the V_(L) is orcomprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:540; the V_(H) isor comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:524, and theV_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:541;the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ IDNO:525, and the V_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 withinSEQ ID NO:261; the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3within SEQ ID NO:526, and the V_(L) is or comprises a CDR-L1, CDR-L2 andCDR-L3 within SEQ ID NO:542; the V_(H) is or comprises a CDR-H1, CDR-H2and CDR-H3 within SEQ ID NO:527, and the V_(L) is or comprises a CDR-L1,CDR-L2 and CDR-L3 within SEQ ID NO:543; the V_(H) is or comprises aCDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:528, and the V_(L) is orcomprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:544; the V_(H) isor comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:529, and theV_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:545;the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ IDNO:528, and the V_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 withinSEQ ID NO:546; the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3within SEQ ID NO:522, and the V_(L) is or comprises a CDR-L1, CDR-L2 andCDR-L3 within SEQ ID NO:547; the V_(H) is or comprises a CDR-H1, CDR-H2and CDR-H3 within SEQ ID NO:256, and the V_(L) is or comprises a CDR-L1,CDR-L2 and CDR-L3 within SEQ ID NO:548; the V_(H) is or comprises aCDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:530, and the V_(L) is orcomprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:549; the V_(H) isor comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:531, and theV_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:550;the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ IDNO:519, and the V_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 withinSEQ ID NO:552; the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3within SEQ ID NO:110, and the V_(L) is or comprises a CDR-L1, CDR-L2 andCDR-L3 within SEQ ID NO:553; the V_(H) is or comprises a CDR-H1, CDR-H2and CDR-H3 within SEQ ID NO:110, and the V_(L) is or comprises a CDR-L1,CDR-L2 and CDR-L3 within SEQ ID NO:118; the V_(H) is or comprises aCDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:533, and the V_(L) is orcomprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:554; the V_(H) isor comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:115, and theV_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:555;the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ IDNO:524, and the V_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 withinSEQ ID NO:556; or the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3within SEQ ID NO:519, and the V_(L) is or comprises a CDR-L1, CDR-L2 andCDR-L3 within SEQ ID NO:557, respectively.

In some embodiments, the V_(H) is or comprises a CDR-H1, CDR-H2 andCDR-H3 within SEQ ID NO:110, and the V_(L) is or comprises a CDR-L1,CDR-L2 and CDR-L3 within SEQ ID NO:116; the V_(H) is or comprises aCDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:110, and the V_(L) is orcomprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:120; the V_(H) isor comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ ID NO:256, and theV_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:267;or the V_(H) is or comprises a CDR-H1, CDR-H2 and CDR-H3 within SEQ IDNO:519, and the V_(L) is or comprises a CDR-L1, CDR-L2 and CDR-L3 withinSEQ ID NO:535. In some embodiments, the V_(H) is or comprises a CDR-H1,CDR-H2 and CDR-H3 within SEQ ID NO:115, and the V_(L) is or comprises aCDR-L1, CDR-L2 and CDR-L3 within SEQ ID NO:536, respectively.

In some embodiments, the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:110 and 116, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the amino acidsequences of SEQ ID NOs:111 and 117, respectively; the V_(H) and V_(L)regions of the antibody or antigen-binding fragment thereof comprise theamino acid sequences of SEQ ID NOs:110 and 118, respectively; the V_(H)and V_(L) regions of the antibody or antigen-binding fragment thereofcomprise the amino acid sequences of SEQ ID NOs:110 and 119,respectively; the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:110 and 120, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the amino acidsequences of SEQ ID NOs:110 and 121, respectively; the V_(H) and V_(L)regions of the antibody or antigen-binding fragment thereof comprise theamino acid sequences of SEQ ID NOs:110 and 122, respectively; the V_(H)and V_(L) regions of the antibody or antigen-binding fragment thereofcomprise the amino acid sequences of SEQ ID NOs:110 and 123,respectively; the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:112 and 124, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the amino acidsequences of SEQ ID NOs:113 and 125, respectively; the V_(H) and V_(L)regions of the antibody or antigen-binding fragment thereof comprise theamino acid sequences of SEQ ID NOs:114 and 126, respectively; the V_(H)and V_(L) regions of the antibody or antigen-binding fragment thereofcomprise the amino acid sequences of SEQ ID NOs:115 and 127,respectively; the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:247 and 257, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the amino acidsequences of SEQ ID NOs:248 and 258, respectively; the V_(H) and V_(L)regions of the antibody or antigen-binding fragment thereof comprise theamino acid sequences of SEQ ID NOs:249 and 259, respectively; the V_(H)and V_(L) regions of the antibody or antigen-binding fragment thereofcomprise the amino acid sequences of SEQ ID NOs:250 and 260,respectively; the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:251 and 261, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the amino acidsequences of SEQ ID NOs:252 and 262, respectively; the V_(H) and V_(L)regions of the antibody or antigen-binding fragment thereof comprise theamino acid sequences of SEQ ID NOs:253 and 263, respectively; the V_(H)and V_(L) regions of the antibody or antigen-binding fragment thereofcomprise the amino acid sequences of SEQ ID NOs:254 and 264,respectively; the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:255 and 265, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the amino acidsequences of SEQ ID NOs:256 and 266, respectively; the V_(H) and V_(L)regions of the antibody or antigen-binding fragment thereof comprise theamino acid sequences of SEQ ID NOs:256 and 267, respectively; the V_(H)and V_(L) regions of the antibody or antigen-binding fragment thereofcomprise the amino acid sequences of SEQ ID NOs:518 and 534,respectively; the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:519 and 535, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the amino acidsequences of SEQ ID NOs:115 and 536, respectively; the V_(H) and V_(L)regions of the antibody or antigen-binding fragment thereof comprise theamino acid sequences of SEQ ID NOs:520 and 264, respectively; the V_(H)and V_(L) regions of the antibody or antigen-binding fragment thereofcomprise the amino acid sequences of SEQ ID NOs:521 and 537,respectively; the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:522 and 538, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the amino acidsequences of SEQ ID NOs:523 and 539, respectively; the V_(H) and V_(L)regions of the antibody or antigen-binding fragment thereof comprise theamino acid sequences of SEQ ID NOs:519 and 540, respectively; the V_(H)and V_(L) regions of the antibody or antigen-binding fragment thereofcomprise the amino acid sequences of SEQ ID NOs:524 and 541,respectively; the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:525 and 261, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the amino acidsequences of SEQ ID NOs:526 and 542, respectively; the V_(H) and V_(L)regions of the antibody or antigen-binding fragment thereof comprise theamino acid sequences of SEQ ID NOs:527 and 543, respectively; the V_(H)and V_(L) regions of the antibody or antigen-binding fragment thereofcomprise the amino acid sequences of SEQ ID NOs:528 and 544,respectively; the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:529 and 545, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the amino acidsequences of SEQ ID NOs:528 and 546, respectively; the V_(H) and V_(L)regions of the antibody or antigen-binding fragment thereof comprise theamino acid sequences of SEQ ID NOs:522 and 547, respectively; the V_(H)and V_(L) regions of the antibody or antigen-binding fragment thereofcomprise the amino acid sequences of SEQ ID NOs:256 and 548,respectively; the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:530 and 549, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the amino acidsequences of SEQ ID NOs:531 and 550, respectively; the V_(H) and V_(L)regions of the antibody or antigen-binding fragment thereof comprise theamino acid sequences of SEQ ID NOs:519 and 552, respectively; the V_(H)and V_(L) regions of the antibody or antigen-binding fragment thereofcomprise the amino acid sequences of SEQ ID NOs:110 and 553,respectively; the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:110 and 118, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the amino acidsequences of SEQ ID NOs:533 and 554, respectively; the V_(H) and V_(L)regions of the antibody or antigen-binding fragment thereof comprise theamino acid sequences of SEQ ID NOs:115 and 555, respectively; the V_(H)and V_(L) regions of the antibody or antigen-binding fragment thereofcomprise the amino acid sequences of SEQ ID NOs:524 and 556,respectively; the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:519 and 557, respectively, or any antibody or antigen-bindingfragment thereof that has at least 90% sequence identity to any of theabove V_(H) and V_(L), such as at least 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity thereto. In some embodiments,the antibody or antigen-binding fragment comprises a V_(H) and a V_(L)regions comprising the sequence having at least 90% identity to SEQ IDNOs:110 and 116, respectively; a V_(H) and a V_(L) regions comprisingthe sequence having at least 90% identity to SEQ ID NOs:110 and 120,respectively; a V_(H) and a V_(L) regions comprising the sequence havingat least 90% identity to SEQ ID NOS:256 and 267, respectively; or aV_(H) and a V_(L) regions comprising the sequence having at least 90%identity to SEQ ID NOS:519 and 535, respectively. In some embodiments,the antibody or antigen-binding fragment comprises a V_(H) and a V_(L)regions comprising the sequence having at least 90% identity to SEQ IDNOs:115 and 536, respectively.

For example, the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof provided therein comprise the aminoacid sequences selected from: SEQ ID NOs:110 and 116; SEQ ID NOs:111 and117; SEQ ID NOs:110 and 118; SEQ ID NOs:110 and 119; SEQ ID NOs:110 and120; SEQ ID NOs:110 and 121; SEQ ID NOs:110 and 122; SEQ ID NOs:110 and123; SEQ ID NOs:112 and 124; SEQ ID NOs:113 and 125; SEQ ID NOs:114 and126; SEQ ID NOs:115 and 127; SEQ ID NOs:247 and 257; SEQ ID NOs:248 and258; SEQ ID NOs:249 and 259; SEQ ID NOs:250 and 260; SEQ ID NOs:251 and261; SEQ ID NOs:252 and 262; SEQ ID NOs:253 and 263; SEQ ID NOs:254 and264; SEQ ID NOs:255 and 265; SEQ ID NOs:256 and 266; SEQ ID NOs:256 and267; SEQ ID NOs:518 and 534; SEQ ID NOs:519 and 535; SEQ ID NOs:115 and536; SEQ ID NOs:520 and 264; SEQ ID NOs:521 and 537; SEQ ID NOs:522 and538; SEQ ID NOs:523 and 539; SEQ ID NOs:519 and 540; SEQ ID NOs:524 and541; SEQ ID NOs:525 and 261; SEQ ID NOs:526 and 542; SEQ ID NOs:527 and543; SEQ ID NOs:528 and 544; SEQ ID NOs:529 and 545; SEQ ID NOs:528 and546; SEQ ID NOs:522 and 547; SEQ ID NOs:256 and 548; SEQ ID NOs:530 and549; SEQ ID NOs:531 and 550; SEQ ID NOs:519 and 552; SEQ ID NOs:110 and553; SEQ ID NOs:110 and 118; SEQ ID NOs:533 and 554; SEQ ID NOs:115 and555; SEQ ID NOs:524 and 556; SEQ ID NOs:519 and 557, respectively.

In some embodiments, the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof provided therein comprise the aminoacid sequences selected from: SEQ ID NOs:110 and 116; SEQ ID NOs:111 and117; SEQ ID NOs:110 and 118; SEQ ID NOs:110 and 120; SEQ ID NOs:110 and121; SEQ ID NOs:112 and 124; SEQ ID NOs:113 and 125; SEQ ID NOs:248 and258; SEQ ID NOs:252 and 262; SEQ ID NOs:253 and 263; SEQ ID NOs:254 and264; SEQ ID NOs:255 and 265; SEQ ID NOs:256 and 266; SEQ ID NOs:256 and267; SEQ ID NOs:518 and 534; SEQ ID NOs:519 and 535; SEQ ID NOs:115 and536; SEQ ID NOs:520 and 264; SEQ ID NOs:521 and 537; and SEQ ID NOs:522and 538, respectively. In some embodiments, the V_(H) and V_(L) regionsof the antibody or antigen-binding fragment thereof provided thereincomprise the amino acid sequences selected from: SEQ ID NOs:110 and 116;SEQ ID NOs:110 and 120; SEQ ID NOs:112 and 124; SEQ ID NOs:256 and 267;SEQ ID NOs:519 and 535; and SEQ ID NOs:115 and 536, respectively. Insome embodiments, the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof provided therein comprise the aminoacid sequences selected from: SEQ ID NOs:256 and 267; and SEQ ID NOs:115and 536, respectively.

In some embodiments, the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the sequences of SEQ IDNOs:110 and 116, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the sequences ofSEQ ID NOs:110 and 120, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the sequences ofSEQ ID NOS:256 and 267, respectively; or the V_(H) and V_(L) regions ofthe antibody or antigen-binding fragment thereof comprise the sequencesof SEQ ID NOS:519 and 535, respectively. In some embodiments, the V_(H)and V_(L) regions of the antibody or antigen-binding fragment thereofcomprise the sequences of SEQ ID NOs:115 and 536, respectively.

In some embodiments, the antibody or antigen binding fragment comprisesone or more heavy chain variable (V_(H)) region and one or more lightchain variable (V_(L)) region, in any order or orientation. In someembodiments, the antibody or antigen-binding fragment comprises a V_(H)region and a V_(L) region, and the V_(H) region is amino-terminal to theV_(L) region. In some embodiments, the antibody or antigen-bindingfragment comprises a V_(H) region and a V_(L) region, and the V_(H)region is carboxy-terminal to the V_(L) region. In some embodiments, theV_(H) region(s) and the V_(L) region(s) are linked directly orindirectly, optionally via a linker.

In some embodiments, the antibody or antigen-binding fragment, e.g.,scFv, may include a V_(H) region or portion thereof, followed by thelinker, followed by a V_(L) region or portion thereof. In someembodiments, the antibody or antigen-binding fragment, e.g., the scFv,may include the V_(L) region or portion thereof, followed by the linker,followed by the V_(H) region or portion thereof.

In some embodiments, the antibody or antigen-binding fragment thereof isa single-chain antibody fragment, such as a single chain variablefragment (scFv) or a diabody or a single domain antibody (sdAb). In someembodiments, the antibody or antigen-binding fragment is a single domainantibody comprising only the V_(H) region. In some embodiments, theantibody or antigen binding fragment is an scFv comprising a heavy chainvariable (V_(H)) region and a light chain variable (V_(L)) region. Insome embodiments, the single-chain antibody fragment (e.g. scFv)includes one or more linkers joining two antibody domains or regions,such as a heavy chain variable (V_(H)) region and a light chain variable(V_(L)) region. The linker typically is a peptide linker, e.g., aflexible and/or soluble peptide linker. Among the linkers are those richin glycine and serine and/or in some cases threonine. In someembodiments, the linkers further include charged residues such as lysineand/or glutamate, which can improve solubility. In some embodiments, thelinkers further include one or more proline.

Accordingly, the provided anti-BCMA antibodies include single-chainantibody fragments, such as scFvs and diabodies, particularly humansingle-chain antibody fragments, typically comprising linker(s) joiningtwo antibody domains or regions, such V_(H) and V_(L) regions. Thelinker typically is a peptide linker, e.g., a flexible and/or solublepeptide linker, such as one rich in glycine and serine.

In some aspects, the linkers rich in glycine and serine (and/orthreonine) include at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, or 99% such amino acid(s). In some embodiments, they includeat least at or about 50%, 55%, 60%, 70%, or 75%, glycine, serine, and/orthreonine. In some embodiments, the linker is comprised substantiallyentirely of glycine, serine, and/or threonine. The linkers generally arebetween about 5 and about 50 amino acids in length, typically between ator about 10 and at or about 30, e.g., 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, and in someexamples between 10 and 25 amino acids in length. Exemplary linkersinclude linkers having various numbers of repeats of the sequence GGGGS(4GS; SEQ ID NO:359) or GGGS (3GS; SEQ ID NO:360), such as between 2, 3,4, and 5 repeats of such a sequence. Exemplary linkers include thosehaving or consisting of an sequence set forth in SEQ ID NO:361(GGGGSGGGGSGGGGS). Exemplary linkers further include those having orconsisting of the sequence set forth in SEQ ID NO:362(GSTSGSGKPGSGEGSTKG).

Accordingly, in some embodiments, the provided embodiments includesingle-chain antibody fragments, e.g., scFvs, comprising one or more ofthe aforementioned linkers, such as glycine/serine rich linkers,including linkers having repeats of GGGS or GGGGS, such as the linkerset forth in SEQ ID NO:361. In some embodiments, the linker has an aminoacid sequence containing the sequence set forth in SEQ ID NO:361.

In some aspects, an scFv provided herein comprises the amino acidsequence selected from any one of SEQ ID NOs:128-139, 268-278, 558-576and 578-583, or has an amino acid sequence having at least at or about90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity tothe amino acid sequence selected from any one of SEQ ID NOs:128-139,268-278, 558-576 and 578-583.

For example, the scFv provided herein comprises the amino acid sequenceselected from any of SEQ ID NOS: 128, 129, 130, 131, 132, 133, 134, 135,136, 137, 138, 139, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277,278, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570,571, 572, 573, 574, 575, 576, 578, 579, 580, 581, 582 and 583, or has anamino acid sequence having at least at or about 90%, 91%, 92%, 93%, 94%,95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequenceselected from any one of SEQ ID NOS: 128, 129, 130, 131, 132, 133, 134,135, 136, 137, 138, 139, 268, 269, 270, 271, 272, 273, 274, 275, 276,277, 278, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569,570, 571, 572, 573, 574, 575, 576, 578, 579, 580, 581, 582 and 583.

In some embodiments, the scFv provided herein comprises the amino acidsequence selected from any of SEQ ID NOS: 128, 129, 130, 132, 133, 136,137, 269, 273, 274, 275, 276, 277, 278, 558, 559, 560, 561, 562 and 563,or has an amino acid sequence having at least at or about 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acidsequence selected from any one of SEQ ID NOS: 128, 129, 130, 132, 133,136, 137, 269, 273, 274, 275, 276, 277, 278, 558, 559, 560, 561, 562 and563. In some embodiments, the scFv provided herein comprises the aminoacid sequence selected from any of SEQ ID NOS: 128, 132, 136, 278, 559and 560, or has an amino acid sequence having at least at or about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to theamino acid sequence selected from any one of SEQ ID NOS: 128, 132, 136,278, 559 and 560. In some embodiments, the scFv provided hereincomprises the amino acid sequence selected from any of SEQ ID NOS: 278and 560 or has an amino acid sequence having at least at or about 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to theamino acid sequence selected from any one of SEQ ID NOS: 278 and 560. Insome embodiments, the scFv comprises the sequence selected from any ofSEQ ID NOs:128, 132, 278 and 502, or an sequence having at least 90%sequence identity to the sequence selected from any of SEQ ID NOs:128,132, 278 and 502. In some embodiments, the scFv comprises the sequenceof SEQ ID NO:560, or an sequence having at least 90% sequence identityto the sequence of SEQ ID NO:560.

Table 2 provides the SEQ ID NOS: of exemplary antibodies orantigen-binding fragments and regions or domains thereof that areprovided herein. In some embodiments, the BCMA-binding antibody orfragment thereof comprises a V_(H) region that comprises the CDR-H1,CDR-H2, and CDR-H3 sequence and a V_(L) region that comprises theCDR-L1, CDR-L2 and CDR-L3 sequence set forth in the SEQ ID NOS: listedin each row of Table 2 below (by Kabat numbering). In some embodiments,the BCMA-binding antibody or fragment thereof comprises a V_(H) regionsequence and a V_(L) region sequence set forth in the SEQ ID NOS: listedin each row of Table 2 below, or an antibody comprising a V_(H) andV_(L) region amino acid sequence that has at least 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the V_(H) regionsequence and the V_(L) region sequence set forth in the SEQ ID NOS:listed in each row of Table 2 below. In some embodiments, theBCMA-binding antibody or fragment thereof comprises a V_(H) regionsequence and a V_(L) region sequence set forth in the SEQ ID NOS: listedin each row of Table 2 below. In some embodiments, the BCMA-bindingantibody or fragment thereof comprises an scFv sequence set forth in theSEQ ID NOS: listed in each row of Table 2 below, or an antibodycomprising an scFv amino acid sequence that has at least 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the scFvsequence set forth in the SEQ ID NOS: listed in each row of Table 2below.

TABLE 2 Sequence identifier (SEQ ID NO) for Exemplary Antibodies andDomains Antigen- binding CDR- CDR- CDR- CDR- CDR- CDR- domain H1 H2 H3L1 L2 L3 V_(H) V_(L) scFv BCMA-1 1 4 7 26 37 47 110 116 128 BCMA-2 2 5 827 38 48 111 117 129 BCMA-3 1 4 7 28 39 49 110 118 130 BCMA-4 1 4 7 2940 50 110 119 1 131 BCMA-5 1 4 7 30 39 51 110 1 120 1 132 BCMA-6 1 4 731 41 52 110 121 133 BCMA-7 1 4 7 32 42 53 110 122 134 BCMA-8 1 4 7 3039 54 110 123 135 BCMA-9 2 5 9 33 43 55 112 124 136 BCMA-10 2 5 10 34 4456 113 125 137 BCMA-11 3 6 11 35 45 57 114 126 138 BCMA-12 2 5 10 36 4658 115 127 139 BCMA-13 140 145 149 174 179 184 247 257 268 BCMA-14 141145 149 174 179 185 248 258 269 BCMA-15 141 145 150 174 179 186 249 259270 BCMA-16 142 146 151 174 179 187 250 260 271 BCMA-17 2 5 152 175 180188 251 261 272 BCMA-18 143 147 153 174 179 189 252 262 273 BCMA-19 144148 154 176 181 190 253 263 274 BCMA-20 3 6 155 177 182 191 254 264 275BCMA-21 2 5 156 174 179 192 255 265 276 BCMA-22 2 5 157 178 183 193 256266 277 BCMA-23 2 5 157 178 183 194 256 267 278 BCMA-24 2 6 376 30 399415 518 534 558 BCMA-25 1 4 7 380 400 416 519 535 559 BCMA-26 2 5 10 3343 421 115 536 560 BCMA-27 3 6 155 177 182 191 520 264 561 BCMA-28 3 372376 381 401 417 521 537 562 BCMA-29 3 6 376 382 402 418 522 538 563BCMA-30 3 6 377 383 403 419 523 539 564 BCMA-31 1 4 7 384 39 54 519 540565 BCMA-32 2 5 10 385 180 58 524 541 566 BCMA-33 2 373 152 175 180 188525 261 567 BCMA-34 3 6 11 386 404 420 526 542 568 BCMA-35 2 5 378 33 43421 527 543 569 BCMA-36 2 5 9 387 405 422 528 544 570 BCMA-37 2 5 9 388406 423 529 545 571 BCMA-38 2 5 9 388 407 424 528 546 572 BCMA-39 3 6376 389 408 425 522 547 573 BCMA-40 2 5 157 390 183 193 256 548 574BCMA-41 2 374 9 391 409 426 530 549 575 BCMA-42 1 4 7 392 40 427 531 550576 BCMA-44 1 4 7 394 39 429 519 552 578 BCMA-45 1 4 7 395 411 430 110553 579 BCMA-46 1 4 7 28 39 49 110 118 130 BCMA-47 2 5 10 396 412 431533 554 580 BCMA-48 2 5 10 396 412 58 115 555 581 BCMA-49 2 5 10 397 413432 524 556 582 BCMA-51 1 4 7 398 414 433 519 557 583 BCMA-52 496 507513 517 532 551 577 587 442 BCMA-55 588 589 590 591 592 593 594 595 478BCMA- 288 290 292 302 304 306 324 326 585 C1, VH-VL BCMA- 288 290 292302 304 306 324 326 328 C1, VL-VH BCMA- 289 291 293 303 305 307 325 327329 C2, VH-VL BCMA- 289 291 293 303 305 307 325 327 586 C2, VL-VH

Among the provided antibodies, e.g. antigen-binding fragments, are humanantibodies. In some embodiments of a provided human anti-BCMA antibody,e.g., antigen-binding fragments, the human antibody contains a V_(H)region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%,or 100% sequence identity to an amino acid sequence encoded by agermline nucleotide human heavy chain V segment, a portion having atleast 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an aminoacid sequence encoded by a germline nucleotide human heavy chain Dsegment, and/or a portion having at least 95%, 96%, 97%, 98%, 99%, or100% sequence identity to an amino acid sequence encoded by a germlinenucleotide human heavy chain J segment; and/or contains a V_(L) regionthat comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or100% sequence identity to an amino acid sequence encoded by a germlinenucleotide human kappa or lambda chain V segment, and/or a portionhaving at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to anamino acid sequence encoded by a germline nucleotide human kappa orlambda chain J segment. In some embodiments, the portion of the V_(H)region corresponds to the CDR-H1, CDR-H2 and/or CDR-H3. In someembodiments, the portion of the V_(H) region corresponds to theframework region 1 (FR1), FR2, FR2 and/or FR4. In some embodiments, theportion of the V_(L) region corresponds to the CDR-L1, CDR-L2 and/orCDR-L3. In some embodiments, the portion of the V_(L) region correspondsto the FR1, FR2, FR2 and/or FR4.

In some embodiments, the human antibody or antigen-binding fragmentthereof, contains a CDR-H1 having at least 95%, 96%, 97%, 98%, 99%, or100% sequence identity to an amino acid sequence of the correspondingCDR-H1 region within a sequence encoded by a germline nucleotide humanheavy chain V segment. For example, the human antibody in someembodiments contains a CDR-H1 having a sequence that is 100% identicalor with no more than one, two or three amino acid differences ascompared to the corresponding CDR-H1 region within a sequence encoded bya germline nucleotide human heavy chain V segment.

In some embodiments, the human antibody or antigen-binding fragmentthereof, contains a CDR-H2 having at least 95%, 96%, 97%, 98%, 99%, or100% sequence identity to an amino acid sequence of the correspondingCDR-H2 region within a sequence encoded by a germline nucleotide humanheavy chain V segment. For example, the human antibody in someembodiments contains a CDR-H2 having a sequence that is 100% identicalor with no more than one, two or three amino acid difference as comparedto the corresponding CDR-H2 region within a sequence encoded by agermline nucleotide human heavy chain V segment.

In some embodiments, the human antibody or antigen-binding fragmentthereof, contains a CDR-H3 having at least 95%, 96%, 97%, 98%, 99%, or100% sequence identity to an amino acid sequence of the correspondingCDR-H3 region within a sequence encoded by a germline nucleotide humanheavy chain V segment, D segment and J segment. For example, the humanantibody in some embodiments contains a CDR-H3 having a sequence that is100% identical or with no more than one, two or three amino aciddifferences as compared to the corresponding CDR-H3 region within asequence encoded by a germline nucleotide human heavy chain V segment, Dsegment and J segment.

In some embodiments, the human antibody or antigen-binding fragmentthereof, contains a CDR-L1 having at least 95%, 96%, 97%, 98%, 99%, or100% sequence identity to an amino acid sequence of the correspondingCDR-L1 region within a sequence encoded by a germline nucleotide humanlight chain V segment. For example, the human antibody in someembodiments contains a CDR-L1 having a sequence that is 100% identicalor with no more than one, two or three amino acid differences ascompared to the corresponding CDR-L1 region within a sequence encoded bya germline nucleotide human light chain V segment.

In some embodiments, the human antibody or antigen-binding fragmentthereof, contains a CDR-L2 having at least 95%, 96%, 97%, 98%, 99%, or100% sequence identity to an amino acid sequence of the correspondingCDR-L2 region within a sequence encoded by a germline nucleotide humanlight chain V segment. For example, the human antibody in someembodiments contains a CDR-L2 having a sequence that is 100% identicalor with no more than one, two or three amino acid difference as comparedto the corresponding CDR-L2 region within a sequence encoded by agermline nucleotide human light chain V segment.

In some embodiments, the human antibody or antigen-binding fragmentthereof, contains a CDR-L3 having at least 95%, 96%, 97%, 98%, 99%, or100% sequence identity to an amino acid sequence of the correspondingCDR-L3 region within a sequence encoded by a germline nucleotide humanlight chain V segment and J segment. For example, the human antibody insome embodiments contains a CDR-L3 having a sequence that is 100%identical or with no more than one, two or three amino acid differencesas compared to the corresponding CDR-L3 region within a sequence encodedby a germline nucleotide human light chain V segment and J segment.

In some embodiments, the human antibody or antigen-binding fragmentthereof, contains a framework region that contains human germline genesegment sequences. For example, in some embodiments, the human antibodycontains a V_(H) region in which the framework region, e.g. FR1, FR2,FR3 and FR4, has at least 95%, 96%, 97%, 98%, 99%, or 100% sequenceidentity to a framework region encoded by a human germline antibodysegment, such as a V segment and/or J segment. In some embodiments, thehuman antibody contains a V_(L) region in which the framework regione.g. FR1, FR2, FR3 and FR4, has at least 95%, 96%, 97%, 98%, 99%, or100% sequence identity to a framework region encoded by a human germlineantibody segment, such as a V segment and/or J segment. For example, insome such embodiments, the framework region sequence contained withinthe V_(H) region and/or V_(L) region differs by no more than 10 aminoacids, such as no more than 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid,compared to the framework region sequence encoded by a human germlineantibody segment.

The antibody or antigen-binding fragment thereof, may contain at least aportion of an immunoglobulin constant region, such as one or moreconstant region domain. In some embodiments, the constant regionsinclude a light chain constant region and/or a heavy chain constantregion 1 (CH1). In some embodiments, the antibody includes a CH2 and/orCH3 domain, such as an Fc region. In some embodiments, the Fc region isan Fc region of a human IgG, such as an IgG1 or IgG4.

Also provided are nucleic acids, e.g., polynucleotides, encoding theantibodies and/or portions, e.g., chains, thereof. Among the providednucleic acids are those encoding the anti-BCMA antibodies (e.g.,antigen-binding fragment) described herein. Also provided are nucleicacids, e.g., polynucleotides, encoding one or more antibodies and/orportions thereof, e.g., those encoding one or more of the anti-BCMAantibodies (e.g., antigen-binding fragment) described herein and/orother antibodies and/or portions thereof, e.g., antibodies and/orportions thereof that binds other target antigens. The nucleic acids mayinclude those encompassing natural and/or non-naturally occurringnucleotides and bases, e.g., including those with backbonemodifications. The terms “nucleic acid molecule”, “nucleic acid” and“polynucleotide” may be used interchangeably, and refer to a polymer ofnucleotides. Such polymers of nucleotides may contain natural and/ornon-natural nucleotides, and include, but are not limited to, DNA, RNA,and PNA. “Nucleic acid sequence” refers to the linear sequence ofnucleotides that comprise the nucleic acid molecule or polynucleotide.

Also provided are vectors containing the nucleic acids, e.g.,polynucleotides, and host cells containing the vectors, e.g., forproducing the antibodies or antigen-binding fragments thereof. Alsoprovided are methods for producing the antibodies or antigen-bindingfragments thereof. The nucleic acid may encode an amino acid sequencecomprising the V_(L) region and/or an amino acid sequence comprising theV_(H) region of the antibody (e.g., the light and/or heavy chains of theantibody). The nucleic acid may encode one or more amino acid sequencecomprising the V_(L) region and/or an amino acid sequence comprising theV_(H) region of the antibody (e.g., the light and/or heavy chains of theantibody). In some embodiments, the nucleic acid, e.g., polynucleotideencodes one or more V_(H) region and/or one or more V_(L) region of theantibody, in any order or orientation. In some embodiments, the nucleicacid, e.g., polynucleotide encodes a V_(H) region and a V_(L) region,and the coding sequence for the V_(H) region is upstream of the codingsequence for the V_(L) region. In some embodiments, the nucleic acid,e.g., polynucleotide encodes a V_(H) region and a V_(L) region, and thecoding sequence for the V_(L) region is upstream of the coding sequencefor the V_(H) region.

In a further embodiment, one or more vectors (e.g., expression vectors)comprising such nucleic acids are provided. In a further embodiment, ahost cell comprising such nucleic acids is provided. In one suchembodiment, a host cell comprises (e.g., has been transformed with) avector comprising a nucleic acid that encodes an amino acid sequencecomprising the V_(H) region of the antibody. In another such embodiment,a host cell comprises (e.g., has been transformed with) (1) a vectorcomprising a nucleic acid that encodes an amino acid sequence comprisingthe V_(L) region of the antibody and an amino acid sequence comprisingthe V_(H) region of the antibody, or (2) a first vector comprising anucleic acid that encodes an amino acid sequence comprising the V_(L)region of the antibody and a second vector comprising a nucleic acidthat encodes an amino acid sequence comprising the V_(H) region of theantibody. In some embodiments, a host cell comprises (e.g., has beentransformed with) one or more vectors comprising one or more nucleicacid that encodes one or more an amino acid sequence comprising one ormore antibodies and/or portions thereof, e.g., antigen-binding fragmentsthereof. In some embodiments, one or more such host cells are provided.In some embodiments, a composition containing one or more such hostcells are provided. In some embodiments, the one or more host cells canexpress different antibodies, or the same antibody. In some embodiments,each of the host cells can express more than one antibody.

Also provided are methods of making the anti-BCMA antibodies (includingantigen-binding fragments). For recombinant production of the anti-BCMAantibody, a nucleic acid sequence or a polynucleotide encoding anantibody, e.g., as described above, may be isolated and inserted intoone or more vectors for further cloning and/or expression in a hostcell. Such nucleic acid sequences may be readily isolated and sequencedusing conventional procedures (e.g., by using oligonucleotide probesthat are capable of binding specifically to genes encoding the heavy andlight chains of the antibody). In some embodiments, a method of makingthe anti-BCMA antibody is provided, wherein the method comprisesculturing a host cell comprising a nucleic acid sequence encoding theantibody, as provided above, under conditions suitable for expression ofthe antibody, and optionally recovering the antibody from the host cell(or host cell culture medium).

In addition to prokaryotes, eukaryotic microbes such as filamentousfungi or yeast are suitable cloning or expression hosts forantibody-encoding vectors, including fungi and yeast strains whoseglycosylation pathways have been modified to mimic or approximate thosein human cells, resulting in the production of an antibody with apartially or fully human glycosylation pattern. See Gerngross, Nat.Biotech. 22:1409-1414 (2004), and Li et al., Nat. Biotech. 24:210-215(2006).

Exemplary eukaryotic cells that may be used to express polypeptidesinclude, but are not limited to, COS cells, including COS 7 cells; 293cells, including 293-6E cells; CHO cells, including CHO-S, DG44. Lec13CHO cells, and FUT8 CHO cells; PER.C6® cells; and NSO cells. In someembodiments, the antibody heavy chains and/or light chains (e.g., V_(H)region and/or V_(L) region) may be expressed in yeast. See, e.g., U.S.Publication No. US 2006/0270045 A1. In some embodiments, a particulareukaryotic host cell is selected based on its ability to make desiredpost-translational modifications to the heavy chains and/or light chains(e.g., V_(H) region and/or V_(L) region). For example, in someembodiments, CHO cells produce polypeptides that have a higher level ofsialylation than the same polypeptide produced in 293 cells.

In some embodiments, the antibody or antigen-binding fragment providedherein is produced in a cell-free system. Exemplary cell-free systemsare described, e.g., in Sitaraman et al., Methods Mol. Biol. 498: 229-44(2009); Spirin, Trends Biotechnol. 22: 538-45 (2004); Endo et al.,Biotechnol. Adv. 21: 695-713 (2003).

The provided embodiments further include vectors and host cells andother expression systems for expressing and producing the antibodies andother antigen-binding proteins, including eukaryotic and prokaryotichost cells, including bacteria, filamentous fungi, and yeast, as well asmammalian cells such as human cells, as well as cell-free expressionsystems.

b. Exemplary Features

In some aspects, the provided antibodies or antigen-binding fragmentsthereof have one or more specified functional features, such as bindingproperties, including binding to particular epitopes.

In some embodiments, the antibodies or antigen-binding fragments thereofspecifically bind to BCMA protein. In some embodiments provided herein,BCMA protein refers to human BCMA, a mouse BCMA protein, or a non-humanprimate (e.g., cynomolgus monkey) BCMA protein. In some embodiments ofany of the embodiments herein, BCMA protein refers to human BCMAprotein. The observation that an antibody or other binding moleculebinds to BCMA protein or specifically binds to BCMA protein does notnecessarily mean that it binds to a BCMA protein of every species. Forexample, in some embodiments, features of binding to BCMA protein, suchas the ability to specifically bind thereto and/or to bind with aparticular affinity to a particular degree, in some embodiments, refersto the ability with respect to a human BCMA protein and the antibody maynot have this feature with respect to a BCMA protein of another species,such as mouse.

In some embodiments, the antibody or antigen-binding fragment binds to amammalian BCMA protein, including to naturally occurring variants ofBCMA, such as certain splice variants or allelic variants.

In some embodiments, the antibodies specifically bind to human BCMAprotein, such as to an epitope or region of human BCMA protein, such asthe human BCMA protein comprising the amino acid sequence of SEQ IDNO:367 (GenBank No. BAB60895.1), or SEQ ID NO:368 (NCBI No. NP 001183.2)or an allelic variant or splice variant thereof. In one embodiment, thehuman BCMA protein is encoded by a transcript variant or is an isoformthat has the sequence of amino acids forth in SEQ ID NO:369. In someembodiments, the antibodies bind to cynomolgus monkey BCMA protein, suchas the cynomolgus monkey BCMA protein set forth in SEQ ID NO:371(GenBank No. EHH60172.1). In some embodiments, the antibodies bind tohuman BCMA but do not bind to or bind in a lower level or degree oraffinity to cynomolgus monkey BCMA protein, such as the cynomolgusmonkey BCMA protein set forth in SEQ ID NO:371 (GenBank No. EHH60172.1).In some embodiments, the antibodies do not bind to or bind in a lowerlevel or degree or affinity to mouse BCMA protein, such as the mouseBCMA protein set forth in SEQ ID NO:370 (NCBI No. NP 035738.1). In someembodiments, the antibodies bind to mouse BCMA protein, such as themouse BCMA protein set forth in SEQ ID NO:370 (NCBI No. NP 035738.1). Insome embodiments, the antibodies bind to mouse BCMA protein, with loweraffinity than its binding to a human BCM protein and/or a cynomolgusmonkey BCMA protein. In some embodiments, the antibodies bind to mouseBCMA protein and/or a cynomolgus monkey BCMA protein with lower affinitythan its binding to a human BCM protein. In some embodiments, theantibodies bind to mouse BCMA protein and/or a cynomolgus monkey BCMAprotein with similar binding affinity compared to its binding to a humanBCMA protein.

In one embodiment, the extent of binding of an anti-BCMA antibody to anunrelated, non-BCMA protein, such as a non-human BCMA protein or othernon-BCMA protein, is less than at or about 10% of the binding of theantibody to human BCMA protein as measured, e.g., by a radioimmunoassay(RIA). In some embodiments, among provided antibodies are antibodies inwhich binding to mouse BCMA protein is less than or at or about 10% ofthe binding of the antibody to human BCMA protein. In some embodiments,among provided antibodies are antibodies in which binding to cynomolgusmonkey BCMA protein is less than or at or about 10% of the binding ofthe antibody to human BCMA protein. In some embodiments, among providedantibodies are antibodies in which binding to cynomolgus monkey BCMAprotein and/or a mouse BCMA protein is similar to or about the same asthe binding of the antibody to human BCMA protein.

In some embodiments, the antibody specifically binds to and/or to bindwith a particular affinity to a particular degree, to a BCMA protein,e.g., human BCMA, a mouse BCMA protein, or a non-human primate (e.g.,cynomolgus monkey) BCMA protein.

In some embodiments, the provided antibodies are capable of binding BCMAprotein, such as human BCMA protein, with at least a certain affinity,as measured by any of a number of known methods. In some embodiments,the affinity is represented by an equilibrium dissociation constant(K_(D)); in some embodiments, the affinity is represented by EC₅₀.

A variety of assays are known for assessing binding affinity and/ordetermining whether a binding molecule (e.g., an antibody or fragmentthereof) specifically binds to a particular ligand (e.g., an antigen,such as a BCMA protein). It is within the level of a skilled artisan todetermine the binding affinity of a binding molecule, e.g., an antibody,for an antigen, e.g., BCMA, such as human BCMA or cynomolgus BCMA ormouse BCMA, such as by using any of a number of binding assays that arewell known in the art. For example, in some embodiments, a BIAcore®instrument can be used to determine the binding kinetics and constantsof a complex between two proteins (e.g., an antibody or fragmentthereof, and an antigen, such as a BCMA protein), using surface plasmonresonance (SPR) analysis (see, e.g., Scatchard et al., Ann. N.Y. Acad.Sci. 51:660, 1949; Wilson, Science 295:2103, 2002; Wolff et al., CancerRes. 53:2560, 1993; and U.S. Pat. Nos. 5,283,173, 5,468,614, or theequivalent).

SPR measures changes in the concentration of molecules at a sensorsurface as molecules bind to or dissociate from the surface. The changein the SPR signal is directly proportional to the change in massconcentration close to the surface, thereby allowing measurement ofbinding kinetics between two molecules. The dissociation constant forthe complex can be determined by monitoring changes in the refractiveindex with respect to time as buffer is passed over the chip. Othersuitable assays for measuring the binding of one protein to anotherinclude, for example, immunoassays such as enzyme linked immunosorbentassays (ELISA) and radioimmunoassays (RIA), or determination of bindingby monitoring the change in the spectroscopic or optical properties ofthe proteins through fluorescence, UV absorption, circular dichroism, ornuclear magnetic resonance (NMR). Other exemplary assays include, butare not limited to, Western blot, ELISA, analytical ultracentrifugation,spectroscopy, flow cytometry, sequencing and other methods for detectionof expressed nucleic acids or binding of proteins.

In some embodiments, the binding molecule, e.g., antibody or fragmentthereof, binds, such as specifically binds, to an antigen, e.g., a BCMAprotein or an epitope therein, with an affinity or K_(A) (i.e., anequilibrium association constant of a particular binding interactionwith units of 1/M; equal to the ratio of the on-rate [k_(on) or k_(a)]to the off-rate [k_(off) or k_(d)] for this association reaction,assuming bimolecular interaction) equal to or greater than 10⁵ M⁻¹. Insome embodiments, the antibody or fragment thereof exhibits a bindingaffinity for the peptide epitope with a K_(D) (i.e., an equilibriumdissociation constant of a particular binding interaction with units ofM; equal to the ratio of the off-rate [k_(off) or k_(d)] to the on-rate[k_(on) or k_(a)] for this association reaction, assuming bimolecularinteraction) of equal to or less than 10⁻⁵ M. For example, theequilibrium dissociation constant K_(D) ranges from 10⁻⁵ M to 10⁻¹³ M,such as 10⁻⁷ M to 10⁻¹¹ M, 10⁻⁸ M to 10⁻¹⁰ M, or 10⁻⁹ M to 10⁻¹⁰ M. Theon-rate (association rate constant; k_(on) or k_(a); units of 1/Ms) andthe off-rate (dissociation rate constant; k_(off) or k_(d); units of1/s) can be determined using any of the assay methods known in the art,for example, surface plasmon resonance (SPR).

In some embodiments, the binding affinity (EC₅₀) and/or the dissociationconstant of the antibody (e.g. antigen-binding fragment) to about BCMAprotein, such as human BCMA protein, is from or from about 0.01 nM toabout 500 nM, from or from about 0.01 nM to about 400 nM, from or fromabout 0.01 nM to about 100 nM, from or from about 0.01 nM to about 50nM, from or from about 0.01 nM to about 10 nM, from or from about 0.01nM to about 1 nM, from or from about 0.01 nM to about 0.1 nM, is from orfrom about 0.1 nM to about 500 nM, from or from about 0.1 nM to about400 nM, from or from about 0.1 nM to about 100 nM, from or from about0.1 nM to about 50 nM, from or from about 0.1 nM to about 10 nM, from orfrom about 0.1 nM to about 1 nM, from or from about 0.5 nM to about 200nM, from or from about 1 nM to about 500 nM, from or from about 1 nM toabout 100 nM, from or from about 1 nM to about 50 nM, from or from about1 nM to about 10 nM, from or from about 2 nM to about 50 nM, from orfrom about 10 nM to about 500 nM, from or from about 10 nM to about 100nM, from or from about 10 nM to about 50 nM, from or from about 50 nM toabout 500 nM, from or from about 50 nM to about 100 nM or from or fromabout 100 nM to about 500 nM. In certain embodiments, the bindingaffinity (EC₅₀) and/or the equilibrium dissociation constant, K_(D), ofthe antibody to a BCMA protein, such as human BCMA protein, is at orless than or about 400 nM, 300 nM, 200 nM, 100 nM, 50 nM, 40 nM, 30 nM,25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM orless. In some embodiments, the antibodies bind to a BCMA protein, suchas human BCMA protein, with a sub-nanomolar binding affinity, forexample, with a binding affinity less than about 1 nM, such as less thanabout 0.9 nM, about 0.8 nM, about 0.7 nM, about 0.6 nM, about 0.5 nM,about 0.4 nM, about 0.3 nM, about 0.2 nM or about 0.1 nM or less.

In some embodiments, the binding affinity may be classified as highaffinity or as low affinity. In some cases, the binding molecule (e.g.antibody or fragment thereof) that exhibits low to moderate affinitybinding exhibits a K_(A) of up to 10⁷M⁻¹, up to 10⁶M⁻¹, up to 10⁵M⁻¹. Insome cases, a binding molecule (e.g. antibody or fragment thereof) thatexhibits high affinity binding to a particular epitope interacts withsuch epitope with a K_(A) of at least 10⁷ M⁻¹, at least 10⁸M⁻¹ at least10⁹M⁻¹ at least 10¹⁰M⁻¹, at least 10¹¹M⁻¹, at least 10¹²M⁻¹ or at least10¹³M⁻¹. In some embodiments, the binding affinity (EC₅₀) and/or theequilibrium dissociation constant, K_(D), of the binding molecule, e.g.,anti-BCMA antibody or fragment thereof, to a BCMA protein, is from orfrom about 0.01 nM to about 1 μM, 0.1 nM to 1 μM, 1 nM to 1 μM, 1 nM to500 nM, 1 nM to 100 nM, 1 nM to 50 nM, 1 nM to 10 nM, 10 nM to 500 nM,10 nM to 100 nM, 10 nM to 50 nM, 50 nM to 500 nM, 50 nM to 100 nM or 100nM to 500 nM. In certain embodiments, the binding affinity (EC₅₀) and/orthe dissociation constant of the equilibrium dissociation constant,K_(D), of the binding molecule, e.g., anti-BCMA antibody or fragmentthereof, to a BCMA protein, is at or about or less than at or about 1μM, 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM or less.

In some embodiments, the binding affinity of a binding molecule, such asan anti-BCMA antibody, for different antigens, e.g., BCMA proteins fromdifferent species can be compared to determine the speciescross-reactivity. For example, species cross-reactivity can beclassified as high cross reactivity or low cross reactivity. In someembodiments, the equilibrium dissociation constant, K_(D), for differentantigens, e.g., BCMA proteins from different species such as human,cynomolgus monkey or mouse, can be compared to determine speciescross-reactivity. In some embodiments, the species cross-reactivity ofan anti-BCMA antibody can be high, e.g., the anti-BCMA antibody binds tohuman BCMA and a species variant BCMA to a similar degree, e.g., theratio of K_(D) for human BCMA and K_(D) for the species variant BCMA isor is about 1. In some embodiments, the species cross-reactivity of ananti-BCMA antibody can be low, e.g., the anti-BCMA antibody has a highaffinity for human BCMA but a low affinity for a species variant BCMA,or vice versa. For example, the ratio of K_(D) for the species variantBCMA and K_(D) for the human BCMA is more than 10, 15, 20, 25, 30, 40,50, 60, 70, 80, 90, 100, 200, 500, 1000, 2000 or more, and the anti-BCMAantibody has low species cross-reactivity. The degree of speciescross-reactivity can be compared with the species cross-reactivity of aknown antibody.

In some embodiments, the provided antibodies or antigen bindingfragments thereof bind to a similar degree to a human BCMA protein and anon-human BCMA protein or other non-BCMA proteins. For example, in someembodiments, the provided antibodies or antigen binding fragmentsthereof bind to a human BCMA protein, such as the human BCMA proteincomprising the amino acid sequence of SEQ ID NO:367 (GenBank No.BAB60895.1), or SEQ ID NO:368 (NCBI No. NP 001183.2) or an allelicvariant or splice variant thereof, with an equilibrium dissociationconstant (K_(D)), and to a non-human BCMA, such as a cynomolgus monkeyBCMA, such as the cynomolgus monkey BCMA protein set forth in SEQ IDNO:371 (GenBank No. EHH60172.1), with a K_(D) that is similar, or aboutthe same, or less than 2-fold different, or less than 5-fold different.

For example, in some embodiments, the provided antibodies or antigenbinding fragments thereof bind to a human BCMA with a K_(D) of about orless than at or about 1 μM, 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 25 nM,20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM or less, andbinds to a cynomolgus monkey BCMA with a K_(D) of about or less than ator about 1 μM, 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM,18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM or less. In someembodiments, the provided antibodies or antigen binding fragmentsthereof bind to a mouse BCMA protein with a K_(D) of about or less thanat or about 1 μM, 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM,8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM or less. In someembodiments, the provided antibodies or antigen binding fragmentsthereof bind to a human BCMA, a cynomolgus monkey BCMA and a mouse BCMAwith high affinity. In some embodiments, the provided antibodies orantigen binding fragments thereof bind to a human BCMA and cynomolgusmonkey BCMA with a high affinity, and to a mouse BCMA with low affinity.In some embodiments, the provided antibodies or antigen bindingfragments thereof bind to a human BCMA and BCMA from other species, orother variants of the BCMA protein, with high affinity.

In some embodiments, the total binding capacity (R_(max)), as measuredusing particular surface plasmon resonance (SPR) conditions, is used todetermine the ability or capacity of binding of the provided antibody orantigen binding fragment thereof, to the antigen, e.g., a BCMA protein,such as a human BCMA protein. For SPR analysis, the “ligand” is theimmobilized target molecule on the surface of the sensor, for example, aBCMA protein, and the “analyte” is the tested molecule, e.g., antibody,for binding to the “ligand”. For example, the “analyte” can be any ofthe provided antibodies or antigen binding fragments thereof that bindsto a BCMA protein. For a particular ligand and analyte pair in SPR, theR_(max) can be determined assuming a 1:1 binding stoichiometry model,for a particular condition. In some embodiments, binding capacity(R_(max)) can be determined using the following formula: R_(max)(RU)=(analyte molecular weight)/(ligand molecular weight)×immobilizedligand level (RU). In particular aspects of SPR conditions, the R_(max)of binding between any of the provided antibody or antigen bindingfragment thereof and a BCMA protein, such as a human BCMA or acynomolgus BCMA, is at least or at least about 50 resonance units (RU),such as about 25 RU, 20 RU, 15 RU, 10 RU, 5 RU or 1 RU.

In some embodiments, the antibodies or antigen-binding fragment thereof,such as the human antibodies, specifically bind to a particular epitopeor region of BCMA protein, such as generally an extracellular epitope orregion. BCMA protein is a type III membrane 184 amino acid protein thatcontains an extracellular domain, a transmembrane domain, and acytoplasmic domain. With reference to a human BCMA amino acid sequenceset forth in SEQ ID NO:367, the extracellular domain corresponds toamino acids 1-54, amino acids 55-77 correspond to the transmembranedomain, and amino acids 78-184 correspond to the cytoplasmic domain.

In some embodiments, the antibodies or antigen-binding fragment thereof,binds, e.g., specifically binds, and/or recognizes, one or more epitopesin BCMA, e.g., human BCMA. In some embodiments, the epitopes areepitopes present on the extracellular domain of BCMA, e.g., human BCMA.In some embodiments, the epitopes include peptide epitopes. In someembodiments, the epitope includes linear epitopes and/or conformationalepitopes or combination thereof. In some embodiments, the epitope(s) onBCMA, that the antibody or antigen-binding fragment thereof, e.g.,anti-BCMA antibody or antigen-binding fragment thereof provided herein,include conformational epitopes, e.g., epitopes that include severalpeptide stretches from BCMA. In some embodiments, the anti-BCMAantibodies or antigen-binding fragment thereof provided herein bind toor recognize one or a combination of ₂₁CIPCQLR₂₇ (set forth in SEQ IDNO:375), ₃₀SNTPPLTCQR₃₉ (set forth in SEQ ID NO:379) and ₄₄SVTNSVK₅₀(set forth in SEQ ID NO:393). In some embodiments, the epitope ofcomprises ₃₀SNTPPLTCQR₃₉ (SEQ ID NO:379) and/or ₄₄SVTNSVK₅₀ (SEQ IDNO:393). In some embodiments, the anti-BCMA antibodies orantigen-binding fragment thereof provided herein bind to or recognize₃₀SNTPPLTCQR₃₉ (set forth in SEQ ID NO:379). In some embodiments, theanti-BCMA antibodies or antigen-binding fragment thereof provided hereinbind to or recognize one or a combination of ₈CSQNEYF₁₄ (set forth inSEQ ID NO:410) and ₁₇LLHACIPCQLR₂₇ (set forth in SEQ ID NO:428). In someembodiments, the epitope comprises ₁₇LLHACIPCQLR₂₇ (SEQ ID NO:428).

In some embodiments, the antibody or antigen-binding fragment binds toone or more epitope(s) of a human BCMA protein selected from among₂₁CIPCQLR₂₇ (SEQ ID NO:375), ₃₀SNTPPLTCQR₃₉ (SEQ ID NO:379) and₄₄SVTNSVK₅₀ (SEQ ID NO:393), but does not include a V_(H) regioncomprising a heavy chain complementarity determining region 1 (CDR-H1),CDR-H2, and/or CDR-H3, respectively, comprising the amino acid sequenceof SEQ ID NOs:496, 507 and/or 513, respectively, and/or the antibody orantigen-binding fragment does not comprise a V_(L) region comprising alight chain complementarity determining region 1 (CDR-L1), CDR-L2,and/or CDR-L3, respectively, comprising the amino acid sequence of SEQID NOs:517, 532 and/or 551; or does include an antibody orantigen-binding fragment thereof that comprises a V_(H) regioncontaining the amino acid sequence set forth in SEQ ID NO:577 or anamino acid sequence that has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%,87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%homology thereto, and/or a V_(L) region containing the amino acidsequence set forth in SEQ ID NO:587 or an amino acid sequence that hasat least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homology thereto.

In some embodiments, the antibody or antigen-binding fragment binds toone or more epitope(s) of a human BCMA protein selected from among₈CSQNEYF₁₄ (SEQ ID NO:410) and ₁₇LLHACIPCQLR₂₇ (SEQ ID NO:428), but doesnot comprise a V_(H) region comprising a heavy chain complementaritydetermining region 1 (CDR-H1), CDR-H2, and/or CDR-H3, respectively,comprising the amino acid sequence of SEQ ID NOs:496, 507 and/or 513,respectively, and/or the antibody or antigen-binding fragment does notcomprise a V_(L) region comprising a light chain complementaritydetermining region 1 (CDR-L1), CDR-L2, and/or CDR-L3, respectively,comprising the amino acid sequence of SEQ ID NOs:517, 532 and/or 551; ordoes include an antibody or antigen-binding fragment thereof thatcomprises a V_(H) region containing the amino acid sequence set forth inSEQ ID NO:577 or an amino acid sequence that has at least 80%, 81%, 82%,83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, or 99% homology thereto, and/or a V_(L) region containing theamino acid sequence set forth in SEQ ID NO:587 or an amino acid sequencethat has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homology thereto.

In some embodiments, the antibody or antigen-binding fragment does notcomprise a V_(H) region comprising a heavy chain complementaritydetermining region 1 (CDR-H1), CDR-H2, and/or CDR-H3, respectively,comprising the amino acid sequence of SEQ ID NOs:496, 507 and/or 513,respectively, and/or the antibody or antigen-binding fragment does notcomprise a V_(L) region comprising a light chain complementaritydetermining region 1 (CDR-L1), CDR-L2, and/or CDR-L3, respectively,comprising the amino acid sequence of SEQ ID NOs:517, 532 and/or 551; ordoes include an antibody or antigen-binding fragment thereof thatcomprises a V_(H) region containing the amino acid sequence set forth inSEQ ID NO:577 or an amino acid sequence that has at least 80%, 81%, 82%,83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, or 99% homology thereto, and/or a V_(L) region containing theamino acid sequence set forth in SEQ ID NO:587 or an amino acid sequencethat has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homology thereto.

In some embodiments, the antibody or antigen-binding fragment does notcomprise a V_(H) region comprising a heavy chain complementaritydetermining region 1 (CDR-H1), CDR-H2, and/or CDR-H3, respectively,comprising the amino acid sequence of SEQ ID NOs:588, 589 and/or 590,respectively, and/or the antibody or antigen-binding fragment does notcomprise a V_(L) region comprising a light chain complementaritydetermining region 1 (CDR-L1), CDR-L2, and/or CDR-L3, respectively,comprising the amino acid sequence of SEQ ID NOs:591, 592 and/or 593; ordoes include an antibody or antigen-binding fragment thereof thatcomprises a V_(H) region containing the amino acid sequence set forth inSEQ ID NO:594 or an amino acid sequence that has at least 80%, 81%, 82%,83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, or 99% homology thereto, and/or a V_(L) region containing theamino acid sequence set forth in SEQ ID NO:595 or an amino acid sequencethat has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%,91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homology thereto.

In some embodiments, the provided antibody or antigen-binding fragmentthereof binds to the epitope of a human BCMA protein comprising₃₀SNTPPLTCQR₃₉ (SEQ ID NO:379) and/or ₄₄SVTNSVK₅₀ (SEQ ID NO:393). Forexample, in some embodiments, the antibody or antigen-binding fragmentthereof comprises a heavy chain complementarity determining region 3(CDR-H3) comprising the amino acid sequence selected from any one of SEQID NOs: 7 and 157, or a CDR-H3 contained within the heavy chain variable(V_(H)) region amino acid sequence selected from any one of SEQ IDNOs:110, 256 and 519, and/or a light chain complementarity determiningregion 3 (CDR-L3) comprising the amino acid sequence selected from anyone of SEQ ID NOs: 47, 51, 194 and 416, or a CDR-L3 contained within thelight chain variable (V_(L)) region amino acid sequence selected fromany one of SEQ ID NOs: 116, 120, 267 and 535. In some embodiments, theantibody or antigen-binding fragment thereof further comprises a heavychain complementarity determining region 1 (CDR-H1) comprising the aminoacid sequence selected from any one of SEQ ID NOs: 1 and 2, or a CDR-H1contained within the heavy chain variable (V_(H)) region amino acidsequence selected from any one of SEQ ID NOs:110, 256 and 519, and/or alight chain complementarity determining region 1 (CDR-L1) comprising theamino acid sequence selected from any one of SEQ ID NOs: 26, 30, 178 and380, or a CDR-L1 contained within the light chain variable (V_(L))region amino acid sequence selected from any one of SEQ ID NOs: 116,120, 267 and 535; a heavy chain complementarity determining region 2(CDR-H2) comprising the amino acid sequence selected from any one of SEQID NOs: 4 or 5, or a CDR-H2 contained within the heavy chain variable(V_(H)) region amino acid sequence selected from any one of SEQ IDNOs:110, 256 and 519, and/or a light chain complementarity determiningregion 2 (CDR-L2) comprising the amino acid sequence selected from anyone of SEQ ID NOs: 37, 39, 183 or 400, or a CDR-L2 contained within thelight chain variable (V_(L)) region amino acid sequence selected fromany one of SEQ ID NOs: 116, 120, 267 and 535. For example, in someembodiments, the antibody or antigen-binding fragment comprises a V_(H)region comprising a CDR-H1, a CDR-H2, and a CDR-H3, respectively,comprising the amino acid sequence of a CDR-H1, a CDR-H2, and a CDR-H3contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs: 110, 256 and 519; and/or a V_(L) region comprising aCDR-L1, a CDR-L2, and a CDR-L3, respectively, comprising the amino acidsequence of a CDR-L1, a CDR-L2, and a CDR-L3 contained within the V_(L)region amino acid sequence selected from any one of SEQ ID NOs: 116,120, 267 and 535.

In some embodiments, the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:110 and 116, respectively; the V_(H) and V_(L) regions of theantibody or antigen-binding fragment thereof comprise the amino acidsequences of SEQ ID NOs:110 and 120, respectively; the V_(H) and V_(L)regions of the antibody or antigen-binding fragment thereof comprise theamino acid sequences of SEQ ID NOs:256 and 267, respectively; or theV_(H) and V_(L) regions of the antibody or antigen-binding fragmentthereof comprise the amino acid sequences of SEQ ID NOs:519 and 535,respectively, or an amino acid sequence that has at least 80%, 81%, 82%,83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%,97%, 98%, or 99% sequence identity thereto, respectively.

In some embodiments, the antibody or antigen-binding fragment binds tothe epitope of a human BCMA protein comprising ₁₇LLHACIPCQLR₂₇ (SEQ IDNO:428). For example, in some embodiments, antibody or antigen-bindingfragment comprises a heavy chain complementarity determining region 3(CDR-H3) comprising the amino acid sequence of SEQ ID NO:10, or a CDR-H3contained within the heavy chain variable (V_(H)) region amino acidsequence of SEQ ID NO:115, and/or a light chain complementaritydetermining region 3 (CDR-L3) comprising the amino acid sequence of SEQID NO:421, or a CDR-L3 contained within the light chain variable (V_(L))region amino acid sequence of SEQ ID NO:536. In some embodiments, theantibody or antigen-binding fragment further comprises: a heavy chaincomplementarity determining region 1 (CDR-H1) comprising the amino acidsequence of SEQ ID NO:2, or a CDR-H1 contained within the heavy chainvariable (V_(H)) region amino acid sequence of SEQ ID NO:115 and/or alight chain complementarity determining region 1 (CDR-L1) comprising theamino acid sequence selected from any one of SEQ ID NOs: 33, or a CDR-L1contained within the light chain variable (V_(L)) region amino acidsequence selected from any one of SEQ ID NOs:536; and/or a heavy chaincomplementarity determining region 2 (CDR-H2) comprising the amino acidsequence of SEQ ID NO:5, or a CDR-H1 contained within the heavy chainvariable (V_(H)) region amino acid sequence of SEQ ID NO:115 and/or alight chain complementarity determining region 2 (CDR-L2) comprising theamino acid sequence selected from any one of SEQ ID NOs:43, or a CDR-L1contained within the light chain variable (V_(L)) region amino acidsequence selected from any one of SEQ ID NOs:536. In some embodiments,antibody or antigen-binding fragment comprises a V_(H) region comprisinga CDR-H1, a CDR-H2, and a CDR-H3, respectively, comprising the aminoacid sequence of a CDR-H1, a CDR-H2, and a CDR-H3 contained within theV_(H) region amino acid sequence of SEQ ID NO:115; and/or a V_(L) regioncomprising a CDR-L1, a CDR-L2, and a CDR-L3, respectively, comprisingthe amino acid sequence of a CDR-L1, a CDR-L2, and a CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:536.

In some embodiments, the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:115 and 536, respectively, or an amino acid sequence that hasat least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%,92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto,respectively.

In some embodiments, properties or features of the provided antibodies(e.g., antigen-binding fragments) are described in relation toproperties observed for another antibody, e.g., a reference antibody. Insome embodiments, the reference antibody is a non-human anti-BCMAantibody, such as a murine or chimeric or humanized anti-BCMA antibody.In some aspects, the reference antibody is the murine antibodydesignated C11D5.3 or A7D12.2 (see, e.g., International PCT Pub. No.WO2010/104949), and/or a fragment derived therefrom such as an scFvfragment thereof, and/or an antibody containing the V_(H) and V_(L)regions of such an antibody and/or the heavy and light chain CDRs ofsuch an antibody. A chimeric antigen receptor (CAR) containing anantigen-binding scFv fragment of C11D5.3 has been demonstrated toeffectively promote antitumor reactivity in a CAR therapy (Carpenter etal., Clin Cancer Res., 2013, 19(8):2048-2060).

For example, in some embodiments, the reference antibody has a V_(H)region containing the amino acid sequence set forth in SEQ ID NO:324, orcomprises CDR-H1, CDR-H2, and/or CDR-H3 within such a sequence, and/orhas a V_(L) region containing the amino acid sequence set forth in SEQID NO:326, or comprises CDR-L1, CDR-L2, and/or CDR-L3 within such asequence. For example, the reference antibody can be an antibody thatcontains a CDR-H1 sequence of DYSIN (SEQ ID NO:288), a CDR-H2 sequenceof WINTETREPAYAYDFRG (SEQ ID NO:290), a CDR-H3 sequence of DYSYAMDY (SEQID NO:292), a CDR-L1 sequence of RASESVTILGSHLIH (SEQ ID NO:302), aCDR-L2 sequence of LASNVQT (SEQ ID NO:304) and/or a CDR-L3 sequence ofLQSRTIPRT (SEQ ID NO:306). In some embodiments, the reference antibodyis an scFv that comprises the sequence of amino acids set forth in SEQID NO:328 or 585. In some embodiments, the reference antibody has aV_(H) region containing the amino acid sequence set forth in SEQ IDNO:325, or comprises CDR-H1, CDR-H2, and/or CDR-H3 within such asequence, and/or has a V_(L) region containing the amino acid sequenceset forth in SEQ ID NO:327, or comprises CDR-L1, CDR-L2, and/or CDR-L3within such a sequence. For example, the reference antibody can be anantibody that contains a CDR-H1 sequence of NFGMN (SEQ ID NO:289), aCDR-H2 sequence of WINTYTGESYFADDFKG (SEQ ID NO:291), a CDR-H3 sequenceof GEIYYGYDGGFAY (SEQ ID NO:293), a CDR-L1 sequence of RASQDVNTAVS (SEQID NO:303), a CDR-L2 sequence of SASYRYT (SEQ ID NO:305) and/or a CDR-L3sequence of QQHYSTPWT (SEQ ID NO:307). In some embodiments, thereference antibody is an scFv that comprises the sequence of amino acidsset forth in SEQ ID NO:329 or 586.

In some embodiments, the provided antibody (e.g., antigen-bindingfragment) contains heavy and light chain CDRs that are distinct from theCDRs present in the reference antibody or antibodies. In someembodiments, the provided antibody contains heavy and light chain CDRsthat are distinct from the CDRs present in the V_(H) region amino acidsequence set forth in SEQ ID NO:324 and/or the V_(L) region amino acidsequence set forth in SEQ ID NO:326. In some embodiments, the providedantibody contains heavy and light chain CDRs that are distinct from theCDRs present in the V_(H) region amino acid sequence set forth in SEQ IDNO:325 and/or the V_(L) region amino acid sequence set forth in SEQ IDNO:327.

In some embodiments, the provided the antibodies or antigen-bindingfragment thereof, binds, e.g., specifically binds, and/or recognizes,one or more epitopes in BCMA, e.g., human BCMA but do not comprise aV_(H) region comprising a heavy chain complementarity determining region1 (CDR-H1), CDR-H2, or CDR-H3, respectively, comprising the amino acidsequence of SEQ ID NOs:496, 507 or 513, respectively, and/or theantibody or antigen-binding fragment do not comprise a V_(L) regioncomprising a light chain complementarity determining region 1 (CDR-L1),CDR-L2, or CDR-L3, respectively, comprising the amino acid sequence ofSEQ ID NOs:517, 532 or 551. In some embodiments, the provided theantibodies or antigen-binding fragment thereof, binds, e.g.,specifically binds, and/or recognizes, one or more epitopes in BCMA,e.g., human BCMA but do not comprise a V_(H) region comprising a heavychain complementarity determining region 1 (CDR-H1), CDR-H2, or CDR-H3,respectively, comprising the amino acid sequence of SEQ ID NOs:588, 589or 590, respectively, and/or the antibody or antigen-binding fragment donot comprise a V_(L) region comprising a light chain complementaritydetermining region 1 (CDR-L1), CDR-L2, or CDR-L3, respectively,comprising the amino acid sequence of SEQ ID NOs:588, 589 or 590. Insome embodiments, the antibody or antigen-binding fragment thereofcontains a distinct V_(H) region and/or V_(L) region from an antibody orantigen-binding fragment thereof comprising a V_(H) region and a V_(L)region amino acid sequence set forth in SEQ ID NOS: 577 and 587,respectively, or SEQ ID NOS: 594 and 595, respectively.

In some embodiments, the antibody or antigen-binding fragment does notcomprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and/or CDR-L3 sequenceshaving at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%identity to the CDR-H1, CDR-H2, CDR-H3 and/or CDR-L1, CDR-L2, CDR-L3sequences contained within an antibody comprising the amino acidsequence of SEQ ID NOs:328, 329, 585 and/or 586.

Among the provided antibodies (e.g., antigen-binding fragments) arethose that compete for binding with and/or bind to the same oroverlapping epitopes of BCMA protein as those bound by a referenceantibody described herein but nonetheless contain distinct CDRs, e.g.,distinct heavy and/or light chain CDR1, CDR2, and CDR3.

Among the provided antibodies (e.g., antigen-binding fragments) arethose that do not compete for binding with and/or bind to a distinctepitope of BCMA protein as those bound by a reference antibody describedherein.

In some embodiments, the reference antibody has a sequence present in anantibody or portion thereof as described herein, such as any of theprovided exemplary antibodies. For example, in some embodiments, thereference antibody contains a CDR-H1 comprising the amino acid sequenceselected from any one of SEQ ID NOs:1-3 and 140-144; a CDR-H2 comprisingthe amino acid sequence selected from any one of SEQ ID NOs:4-6, 145-148and 372-374; a CDR-H3 comprising the amino acid sequence selected fromany one of SEQ ID NOs:7-11, 149-157, 279-287 and 376-378; a CDR-L1comprising the amino acid sequence selected from any one of SEQ IDNOs:26-36, 174-178, 380-392 and 394-398; CDR-L2 comprising the aminoacid sequence selected from any one of SEQ ID NOs:37-46, 179-183,399-409 and 411-414; and/or a CDR-L3 comprising the amino acid sequenceselected from any one of SEQ ID NOs:47-58, 184-194, 415-427 and 429-433.For example, in some embodiments, the reference antibody has a V_(L)region amino acid sequence selected from any one of SEQ ID NOs:116-127,257-267, 534-550 and 552-557 and/or has a V_(H) region amino acidsequence selected from any one of SEQ ID NOs:110-115, 247-256, 518-531and 533. In some such embodiments, the antibody has heavy and/or lightchain CDRs 1, 2, and/or 3 as present in such an antibody.

In some embodiments, the antibodies (e.g., antigen-binding fragment)display a binding preference for BCMA-expressing cells as compared toBCMA-negative cells, such as particular cells known and/or describedherein to express BCMA and known not to express BCMA. In someembodiments, the binding preference is observed where a significantlygreater degree of binding is measured to the BCMA-expressing, ascompared to the non-expressing cells. In some embodiments, the foldchange in degree of binding detected, for example, as measured by meanfluorescence intensity in a flow cytometry-based assay and/ordissociation constant or EC₅₀, to the BCMA-expressing cells as comparedto the non-BCMA-expressing cells, is at least at or about 1.5, 2, 3, 4,5, 6, or more, and/or is about as great, about the same, at least asgreat or at least about as great, or greater, than the fold changeobserved for the corresponding form of the reference antibody. In somecases, the total degree of observed binding to BCMA or to theBCMA-expressing cells is approximately the same, at least as great as,or greater than that observed for the corresponding form of thereference antibody.

In some embodiments, the antibody (e.g., antigen-binding fragment)specifically binds to an epitope that overlaps with the epitope of BCMAprotein bound by a reference antibody. In some aspects, among suchantibodies are antibodies that bind to the same or a similar epitope asthe reference antibody. In some embodiments, two antibodies specificallybind to the same epitope and/or an overlapping epitope if all oressentially all amino acid mutations in the antigen that reduce oreliminate binding of one antibody reduce or eliminate binding of theother antibody.

In some embodiments, the antibody (e.g., antigen-binding fragment)specifically binds to an epitope that does not overlap with the epitopeof BCMA protein bound by a reference antibody. In some aspects, amongsuch antibodies are antibodies that bind to a different epitope as thereference antibody. In some embodiments, two antibodies specificallybind to the different epitope if all or essentially all amino acidmutations in the antigen that reduce or eliminate binding of oneantibody do not reduce or eliminate binding of the other antibody.

An antibody “competes for binding” to BCMA protein with a referenceantibody if it competitively inhibits binding of the reference antibodyto BCMA protein, and/or if the reference antibody competitively inhibitsbinding of the antibody to BCMA protein. An antibody competitivelyinhibits binding of a reference antibody to an antigen if the presenceof the antibody in excess detectably inhibits (blocks) binding of theother antibody to its antigen. A particular degree of inhibition may bespecified.

Competitive inhibition assays are known and include ELISA-based, flowcytometry-based assays, and RIA-based assays. In some aspects,competitive inhibition assays are carried out by incorporating an excessof an unlabeled form of one of the antibodies and assessing its abilityto block binding of the other antibody, which is labeled with adetectable marker, such that degree of binding and reduction thereof canbe assessed by detection of the label or marker. In some examples,competitive binding can be measured using assays for molecularinteraction and binding kinetics, such as surface plasmon resonanceanalysis.

Anti-BCMA antibodies (e.g., antigen-binding fragments) provided hereinmay be identified, screened for, or characterized for theirphysical/chemical properties and/or biological activities by variousknown assays. In one aspect, the antibody is tested for its antigenbinding activity, e.g., by known methods such as ELISA, Westernblotting, and/or flow cytometric assays, including cell-based bindingassays, for example, assessing binding of the antibody (e.g., conjugatedto a fluorescent marker or tagged) to a cell expressing the targetantigen, e.g., BCMA, in some cases compared to results using cells thatdo not express the target antigen, e.g., BCMA. Binding affinity may bemeasured as K_(D) or EC₅₀. In some examples, binding affinity, bindingkinetics, and/or binding constants can be measured using assays todetermine molecular interaction, such as surface plasmon resonanceanalysis.

Competition assays may be used to identify an antibody that competeswith any of the antibodies (e.g., antigen-binding fragments) describedherein. Assays for mapping epitopes bound by the antibodies andreference antibodies also may be used and are known.

c. Immunoconjugates

In some embodiments, the antibody (e.g., antigen-binding fragment) is oris part of an immunoconjugate, in which the antibody is conjugated toone or more heterologous molecule(s) or moiety, such as, but not limitedto, a cytotoxic or an imaging agent. Cytotoxic agents include, but arenot limited to, radioactive isotopes (e.g., At²¹¹, I¹³¹, Y⁹⁰, Re¹⁸⁶,Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu);chemotherapeutic agents (e.g., methotrexate, adriamycin, vinca alkaloids(vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycinC, chlorambucil, daunorubicin or other intercalating agents); growthinhibitory agents; enzymes and fragments thereof such as nucleolyticenzymes; antibiotics; toxins such as small molecule toxins orenzymatically active toxins. In some embodiments, the antibody isconjugated to one or more cytotoxic agents, such as chemotherapeuticagents or drugs, growth inhibitory agents, toxins (e.g., protein toxins,enzymatically active toxins of bacterial, fungal, plant, or animalorigin, or fragments), or radioactive isotopes.

Among the immunoconjugates are antibody-drug conjugates (ADCs), in whichan antibody is conjugated to one or more drugs, including but notlimited to a maytansinoid (see U.S. Pat. Nos. 5,208,020, 5,416,064 andEuropean Patent EP 0 425 235 B1); an auristatin such as monomethylauristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Pat. Nos.5,635,483 and 5,780,588, and 7,498,298); a dolastatin; a calicheamicinor derivative thereof (see U.S. Pat. Nos. 5,712,374, 5,714,586,5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296;Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., CancerRes. 58:2925-2928 (1998)); an anthracycline such as daunomycin ordoxorubicin (see Kratz et al., Current Med. Chem. 13:477-523 (2006);Jeffrey et al., Bioorganic & Med Chem. Letters 16:358-362 (2006); Torgovet al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad.Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem.Letters 12:1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343(2002); and U.S. Pat. No. 6,630,579); methotrexate; vindesine; a taxanesuch as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; atrichothecene; and CC1065.

Also among the immunoconjugates are those in which the antibody (e.g.,antigen-binding fragment) is conjugated to an enzymatically active toxinor fragment thereof, including but not limited to diphtheria A chain,nonbinding active fragments of diphtheria toxin, exotoxin A chain (fromPseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain,alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolacaamericana proteins (PAPI, PAPII, and PAP-S), Momordica charantiainhibitor, curcin, crotin, Sapaonaria officinalis inhibitor, gelonin,mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.

Also among the immunoconjugates are those in which the antibody (e.g.,antigen-binding fragment) is conjugated to a radioactive atom to form aradioconjugate. Exemplary radioactive isotopes include At²¹¹, I¹³¹,I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactiveisotopes of Lu.

Conjugates of an antibody (e.g., antigen-binding fragment) and cytotoxicagent may be made using any of a number of known protein couplingagents, e.g., linkers, (see Vitetta et al., Science 238:1098 (1987),WO94/11026). In some embodiments, the linker is a peptide or apolypeptide or is a chemical linker. In some embodiments, the linker isa releasable linker or a cleavable linker. The linker may be a“cleavable linker” or a “releasable linker” facilitating release of acytotoxic drug in the cell, such as acid-labile linkers,peptidase-sensitive linkers, photolabile linkers, dimethyl linkers, anddisulfide-containing linkers (Chari et al., Cancer Res. 52:127-131(1992); U.S. Pat. No. 5,208,020). In some embodiments, the releasablelinker or the cleavable linker is released or cleaved in the presence ofone or more conditions or factors present in the tumor microenvironment(TME), including includes matrix metalloproteinase (MMP), hypoxicconditions or acidic conditions.

d. Multispecific Antibodies

In certain embodiments, the BCMA-binding molecules, e.g., antibodies orpolypeptides such as chimeric receptors containing the same, aremultispecific. Among the multispecific binding molecules aremultispecific antibodies, including, e.g. bispecific or trispecificantibodies. Multispecific binding partners, e.g., antibodies, havebinding specificities for at least two different sites, which may be inthe same or different antigens. In certain embodiments, one of thebinding specificities is for BCMA and the other is for another antigen.In some embodiments, additional binding molecules bind to and/orrecognize a third, or more antigens. In certain embodiments, bispecificantibodies may bind to two different epitopes of BCMA. Bispecificantibodies may also be used to localize cytotoxic agents to cells whichexpress BCMA. Bispecific antibodies can be prepared as full lengthantibodies or antibody fragments. Among the multispecific antibodies aremultispecific single-chain antibodies, e.g., diabodies, triabodies, andtetrabodies, tandem di-scFvs, and tandem tri-scFvs. Also provided aremultispecific chimeric receptors, such as multispecific CARs, containingthe antibodies (e.g., antigen-binding fragments). Also provided aremultispecific cells containing the antibodies or polypeptides includingthe same, such as cells containing a cell surface protein including theanti-BCMA antibody and an additional cell surface protein, such as anadditional chimeric receptor, which binds to a different antigen or adifferent epitope on BCMA.

Exemplary antigens include B cell specific antigens, othertumor-specific antigens, such as antigens expressed specifically on orassociated with a leukemia (e.g., B cell leukemia), lymphoma (e.g.,Hodgkin's lymphoma, non-Hodgkin's lymphoma, etc.), or a myeloma, e.g., amultiple myeloma (MM), a plasma cell malignancy (e.g., plasmacytoma).For example, antigens include those expressed specifically on orassociated with B cell chronic lymphocytic leukemia (CLL), a diffuselarge B-cell lymphoma (DLBCL), acute myeloid leukemia (AML), acutelymphocytic leukemia (ALL), Burkitt's lymphoma (e.g., endemic Burkitt'slymphoma or sporadic Burkitt's lymphoma), mantle cell lymphoma (MCL),non-small cell lung cancer (NSCLC), chronic myeloid (or myelogenous)leukemia (CML), hairy cell leukemia (HCL), small lymphocytic lymphoma(SLL), Marginal zone lymphoma, Hodgkin lymphoma (HL), non-Hodgkinlymphoma (NHL), Anaplastic large cell lymphoma (ALCL), refractoryfollicular lymphoma, Waldenstrom macroglobulinemia, follicular lymphoma,small non-cleaved cell lymphoma, mucosa-associated lymphatic tissuelymphoma (MALT), marginal zone lymphoma, nodal monocytoid B celllymphoma, immunoblastic lymphoma, large cell lymphoma, diffuse mixedcell lymphoma, pulmonary B cell angiocentric lymphoma, small lymphocyticlymphoma, primary mediastinal B cell lymphoma, lymphoplasmacyticlymphoma (LPL), neuroblastoma, renal cell carcinoma, colon cancer,colorectal cancer, breast cancer, epithelial squamous cell cancer,melanoma, myeloma such as multiple myeloma (e.g., non-secretory multiplemyeloma, smoldering multiple myeloma), stomach cancer, esophagealcancer, brain cancer, lung cancer (e.g., small-cell lung cancer),pancreatic cancer, cervical cancer, ovarian cancer, liver cancer (e.g.,hepatic carcinoma, hepatoma, etc.), bladder cancer, prostate cancer,testicular cancer, thyroid cancer, uterine cancer, spleen cancer (e.g.,splenic lymphoma), adrenal cancer and/or head and neck cancer, andantigens expressed on T cells.

In some embodiments, among the second or additional antigens formulti-targeting strategies includes those in which at least one of theantigens is a universal tumor antigen, or a family member thereof. Insome embodiments, the second or additional antigen is an antigenexpressed on a tumor. In some embodiments, the BCMA-binding moleculesprovided herein target an antigen on the same tumor type as the secondor additional antigen. In some embodiments, the second or additionalantigen may also be a universal tumor antigen or may be a tumor antigenspecific to a tumor type.

Exemplary second or additional antigens include CD4, CD5, CD8, CD14,CD15, CD19, CD20, CD21, CD22, CD23, CD25, CD33, CD37, CD38, CD40, CD40L,CD46, CD52, CD54, CD74, CD80, CD126, CD138, B7, MUC-1, Ia, HM1.24,HLA-DR, tenascin, an angiogenesis factor, VEGF, PIGF, ED-B fibronectin,an oncogene, an oncogene product, CD66a-d, necrosis antigens, Ii, IL-2,T101, TAC, IL-6, ROR1, TRAIL-R1 (DR4), TRAIL-R2 (DR5), tEGFR, Her2,L1-CAM, mesothelin, CEA, hepatitis B surface antigen, anti-folatereceptor, CD24, CD30, CD44, EGFR, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3,ErbB4, erbB dimers, EGFR vIII, FBP, FCRLS, FCRHS, fetal acetylcholinereceptor, GD2, GD3, G protein-coupled receptor class C group 5 member D(GPRCSD), HMW-MAA, IL-22R-alpha, IL-13R-alpha2, kdr, kappa light chain,Lewis Y, L1-cell adhesion molecule (L1-CAM), Melanoma-associated antigen(MAGE)-A1, MAGE-A3, MAGE-A6, Preferentially expressed antigen ofmelanoma (PRAME), survivin, EGP2, EGP40, TAG72, B7-H6, IL-13 receptor a2(IL-13Ra2), CA9, CD171, G250/CAIX, HLA-AI MAGE A1, HLA-A2 NY-ESO-1,PSCA, folate receptor-a, CD44v6, CD44v7/8, avb6 integrin, 8H9, NCAM,VEGF receptors, 5T4, Foetal AchR, NKG2D ligands, dual antigen, anantigen associated with a universal tag, a cancer-testes antigen, MUC1,MUC16, NY-ESO-1, MART-1, gp100, oncofetal antigen, VEGF-R2,carcinoembryonic antigen (CEA), prostate specific antigen, PSMA,Her2/neu, estrogen receptor, progesterone receptor, ephrinB2, CD123,c-Met, GD-2, O-acetylated GD2 (OGD2), CE7, Wilms Tumor 1 (WT-1), acyclin, cyclin A2, CCL-1, hTERT, MDM2, CYP1B, WT1, livin, AFP, p53,cyclin (D1), CS-1, BAFF-R, TACI, CD56, TIM-3, CD123, L1-cell adhesionmolecule, MAGE-A1, MAGE A3, a cyclin, such as cyclin A1 (CCNA1) and/or apathogen-specific antigen, biotinylated molecules, molecules expressedby HIV, HCV, HBV and/or other pathogens, and/or in some aspects,neoepitopes or neoantigens thereof. In some embodiments, the antigen isassociated with or is a universal tag.

In some aspects, the antigen, e.g., the second or additional antigen,such as the disease-specific antigen and/or related antigen, isexpressed on multiple myeloma, such as G protein-coupled receptor classC group 5 member D (GPRCSD), CD38 (cyclic ADP ribose hydrolase), CD138(syndecan-1, syndecan, SYN-1), CS-1 (CS1, CD2 subset 1, CRACC, SLAMF7,CD319, and 19A24), BAFF-R, TACI and/or FcRH5. Other exemplary multiplemyeloma antigens include CD56, TIM-3, CD33, CD123, CD44, CD20, CD40,CD74, CD200, EGFR, β2-Microglobulin, HM1.24, IGF-1R, IL-6R, TRAIL-R1,and the activin receptor type IIA (ActRIIA). See Benson and Byrd, J.Clin. Oncol. (2012) 30(16): 2013-15; Tao and Anderson, Bone MarrowResearch (2011):924058; Chu et al., Leukemia (2013) 28(4):917-27;Garfall et al., Discov Med. (2014) 17(91):37-46. In some embodiments,the antigens include those present on lymphoid tumors, myeloma,AIDS-associated lymphoma, and/or post-transplant lymphoproliferations,such as CD38. Antibodies or antigen-binding fragments directed againstsuch antigens are known and include, for example, those described inU.S. Pat. Nos. 8,153,765; 8,603,477, 8,008,450; U.S. Pub. No.US20120189622 or US20100260748; and/or International PCT PublicationNos. WO2006099875, WO2009080829 or WO2012092612 or WO2014210064. In someembodiments, such antibodies or antigen-binding fragments thereof (e.g.scFv) are contained in multispecific antibodies, multispecific chimericreceptors, such as multispecific CARs, and/or multispecific cells.

e. Variants

In certain embodiments, the antibodies (e.g., antigen-binding fragment)include one or more amino acid variations, e.g., substitutions,deletions, insertions, and/or mutations, compared to the sequence of anantibody described herein. Exemplary variants include those designed toimprove the binding affinity and/or other biological properties of theantibody. Amino acid sequence variants of an antibody may be prepared byintroducing appropriate modifications into the nucleotide sequenceencoding the antibody, or by peptide synthesis. Such modificationsinclude, for example, deletions from, and/or insertions into and/orsubstitutions of residues within the amino acid sequences of theantibody. Any combination of deletion, insertion, and substitution canbe made to arrive at the final construct, provided that the finalconstruct possesses the desired characteristics, e.g., antigen-binding.

In certain embodiments, the antibodies (e.g. antigen-binding fragment)include one or more amino acid substitutions, e.g., as compared to anantibody sequence described herein and/or compared to a sequence of anatural repertoire, e.g., human repertoire. Sites of interest forsubstitutional mutagenesis include the CDRs and FRs. Amino acidsubstitutions may be introduced into an antibody of interest and theproducts screened for a desired activity, e.g., retained/improvedantigen binding, decreased immunogenicity, improved half-life, and/orimproved effector function, such as the ability to promoteantibody-dependent cellular cytotoxicity (ADCC) or complement-dependentcytotoxicity (CDC).

In some embodiments, one or more residues within a CDR of a parentantibody (e.g. a humanized or human antibody) is/are substituted. Insome embodiments, the substitution is made to revert a sequence orposition in the sequence to a germline sequence, such as an antibodysequence found in the germline (e.g., human germline), for example, toreduce the likelihood of immunogenicity, e.g., upon administration to ahuman subject.

In some embodiments, alterations are made in CDR “hotspots,” residuesencoded by codons that undergo mutation at high frequency during thesomatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol.207:179-196 (2008)), and/or residues that contact antigen, with theresulting variant V_(H) or V_(L) being tested for binding affinity.Affinity maturation by constructing and reselecting from secondarylibraries has been described, e.g., in Hoogenboom et al. in Methods inMolecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa,NJ, (2001)). In some embodiments of affinity maturation, diversity isintroduced into the variable genes chosen for maturation by any of avariety of methods (e.g., error-prone PCR, chain shuffling, oroligonucleotide-directed mutagenesis). A secondary library is thencreated. The library is then screened to identify any antibody variantswith the desired affinity. Another method to introduce diversityinvolves CDR-directed approaches, in which several CDR residues (e.g.,4-6 residues at a time) are randomized. CDR residues involved in antigenbinding may be specifically identified, e.g., using alanine scanningmutagenesis or modeling. CDR-H3 and CDR-L3 in particular are oftentargeted.

In certain embodiments, substitutions, insertions, or deletions mayoccur within one or more CDRs so long as such alterations do notsubstantially reduce the ability of the antibody to bind antigen. Forexample, conservative alterations (e.g., conservative substitutions asprovided herein) that do not substantially reduce binding affinity maybe made in CDRs. Such alterations may, for example, be outside ofantigen contacting residues in the CDRs. In certain embodiments of thevariant V_(H) region and V_(L) region sequences provided above, each CDReither is unaltered, or contains no more than one, two or three aminoacid substitutions.

Amino acid sequence insertions include amino- and/or carboxyl-terminalfusions ranging in length from one residue to polypeptides containing ahundred or more residues, as well as intrasequence insertions of singleor multiple amino acid residues. Examples of terminal insertions includean antibody with an N-terminal methionyl residue. Other insertionalvariants of the antibody molecule include the fusion to the N- orC-terminus of the antibody to an enzyme or a polypeptide which increasesthe serum half-life of the antibody.

f. Modifications

In certain embodiments, the antibody is altered to increase or decreasethe extent to which the antibody is glycosylated, for example, byremoving or inserting one or more glycosylation sites by altering theamino acid sequence and/or by modifying the oligosaccharide(s) attachedto the glycosylation sites, e.g., using certain cell lines. In someembodiments, an N-linked glycosylation, which is a glycosylation sitethat occurs at asparagines in the consensus sequence -Asn-Xaa-Ser/Thr isremoved or inserted.

Exemplary modifications, variants, and cell lines are described, e.g.,in Patent Publication Nos. US 2003/0157108, US 2004/0093621, US2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO2005/035586; WO 2005/035778; WO2005/053742; WO2002/031140; Okazaki etal. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech.Bioeng. 87: 614 (2004). Ripka et al. Arch. Biochem. Biophys. 249:533-545(1986); US Pat Appl No US 2003/0157108 A1, Presta, L; and WO 2004/056312A1, Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. etal., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO2003/085107); WO2003/011878 (Jean-Mairet et al.); U.S. Pat. No. 6,602,684 (Umana etal.); and US 2005/0123546 (Umana et al.); WO 1997/30087 (Patel et al.);WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).

Among the modified antibodies are those having one or more amino acidmodifications in the Fc region, such as those having a human Fc regionsequence or other portion of a constant region (e.g., a human IgG1,IgG2, IgG3 or IgG4 Fc region) comprising an amino acid modification(e.g. a substitution) at one or more amino acid positions.

Such modifications can be made, e.g., to improve half-life, alterbinding to one or more types of Fc receptors, and/or alter effectorfunctions.

Also among the variants are cysteine engineered antibodies such as“thioMAbs” and other cysteine engineered variants, in which one or moreresidues of an antibody are substituted with cysteine residues, in orderto generate reactive thiol groups at accessible sites, e.g., for use inconjugation of agents and linker-agents, to produce immunoconjugates.Cysteine engineered antibodies are described, e.g., in U.S. Pat. Nos.7,855,275 and 7,521,541.

In some embodiments, the antibodies (e.g., antigen-binding fragment) aremodified to contain additional nonproteinaceous moieties, includingwater soluble polymers. Exemplary polymers include, but are not limitedto, polyethylene glycol (PEG), copolymers of ethylene glycol/propyleneglycol, carboxymethylcellulose, dextran, polyvinyl alcohol,polyvinylpyrrolidone, poly-1, 3-dioxolane, poly-1,3,6-trioxane,ethylene/maleic anhydride copolymer, polyamino acids (eitherhomopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, polypropylene glycol homopolymers,polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols(e.g., glycerol), polyvinyl alcohol, and mixtures thereof. Polyethyleneglycol propionaldehyde may have advantages in manufacturing due to itsstability in water. The polymer may be of any molecular weight, and maybe branched or unbranched. The number of polymers attached to theantibody may vary, and if more than one polymer is attached, they can bethe same or different molecules. In general, the number and/or type ofpolymers used for derivatization can be determined based onconsiderations including, but not limited to, the particular propertiesor functions of the antibody to be improved, whether the antibodyderivative will be used in a therapy under defined conditions, etc.

B. Recombinant Receptors

Also among the binding molecules are polypeptides containing any suchantibodies or antigen-binding fragments provided herein, includingsingle chain cell surface proteins, e.g., recombinant receptors, such aschimeric antigen receptors containing such antibodies or antigen-bindingfragments. Among the provided binding molecules (e.g., BCMA-bindingmolecules) are single chain cell surface proteins, such as recombinantreceptors (e.g., antigen receptors), that include one of the providedantibodies (e.g., antigen-binding fragment). The recombinant receptorsinclude antigen receptors that specifically bind to BCMA, such asantigen receptors containing the provided anti-BCMA antibodies, e.g.,antigen-binding fragments. Among the antigen receptors are functionalnon-TCR antigen receptors, such as chimeric antigen receptors (CARs).Also provided are cells expressing the recombinant receptors and usesthereof in adoptive cell therapy, such as treatment of diseases anddisorders associated with BCMA expression.

Exemplary antigen receptors, including CARs, and methods for engineeringand introducing such antigen receptors into cells, include thosedescribed, for example, in international patent application publicationNos. WO200014257, WO2013126726, WO2012/129514, WO2014031687,WO2013/166321, WO2013/071154, WO2013/123061 U.S. patent applicationpublication Nos. US2002131960, US2013287748, US20130149337, U.S. Pat.Nos. 6,451,995, 7,446,190, 8,252,592, 8,339,645, 8,398,282, 7,446,179,6,410,319, 7,070,995, 7,265,209, 7,354,762, 7,446,191, 8,324,353, and8,479,118, and European patent application No. EP2537416, and/or thosedescribed by Sadelain et al., Cancer Discov. 2013 April; 3(4): 388-398;Davila et al. (2013) PLoS ONE 8(4): e61338; Turtle et al., Curr. Opin.Immunol., 2012 October; 24(5): 633-39; Wu et al., Cancer, 2012 March18(2): 160-75. In some aspects, the antigen receptors include a CAR asdescribed in U.S. Pat. No. 7,446,190, and those described inInternational Patent Application Publication No. WO/2014055668 A1.Exemplary CARs include CARs as disclosed in any of the aforementionedpublications, such as WO2014031687, U.S. Pat. Nos. 8,339,645, 7,446,179,US 2013/0149337, U.S. Pat. Nos. 7,446,190, 8,389,282, e.g., and in whichthe antigen-binding portion, e.g., scFv, is replaced by an antibody oran antigen-binding fragment thereof, e.g., as provided herein.

Among the chimeric receptors are chimeric antigen receptors (CARs). Thechimeric receptors, such as CARs, generally include an extracellularantigen binding domain that includes, is, or is comprised within, one ofthe provided anti-BCMA antibodies. Thus, the chimeric receptors, e.g.,CARs, typically include in their extracellular portions one or moreBCMA-binding molecules, such as one or more antigen-binding fragment,domain, or portion, or one or more antibody variable regions, and/orantibody molecules, such as those described herein. In some embodiments,the CAR includes a BCMA-binding portion or portions of the antibodymolecule, such as a heavy chain variable (V_(H)) region and/or lightchain variable (V_(L)) region of the antibody, e.g., an scFv antibodyfragment.

BCMA-targeting CARs are described, for example, by Carpenter et al.,Clin Cancer Res., 2013, 19(8):2048-2060.

In some embodiments, the recombinant receptor such as a CAR comprisingan antibody (e.g., antigen-binding fragment) provided herein, furtherincludes a spacer, which may be or include at least a portion of animmunoglobulin constant region or variant or modified version thereof,such as a hinge region, e.g., an IgG4 hinge region, and/or a CH1/CLand/or Fc region. In some embodiments, the constant region or portion isof a human IgG, such as IgG4 or IgG1. In some aspects, the portion ofthe constant region serves as a spacer region between theantigen-recognition component (e.g., scFv) and transmembrane domain. Thespacer can be of a length that provides for increased responsiveness ofthe cell following antigen binding, as compared to in the absence of thespacer. In some examples, the spacer is at or about 12 amino acids inlength or is no more than 12 amino acids in length. Exemplary spacersinclude those having at least about 10 to 229 amino acids, about 10 to200 amino acids, about 10 to 175 amino acids, about 10 to 150 aminoacids, about 10 to 125 amino acids, about 10 to 100 amino acids, about10 to 75 amino acids, about 10 to 50 amino acids, about 10 to 40 aminoacids, about 10 to 30 amino acids, about 10 to 20 amino acids, or about10 to 15 amino acids, and including any integer between the endpoints ofany of the listed ranges. In some embodiments, a spacer region has about12 amino acids or less, about 119 amino acids or less, or about 229amino acids or less. Exemplary spacers include IgG4 hinge alone, IgG4hinge linked to CH2 and CH3 domains, or IgG4 hinge linked to the CH3domain. Exemplary spacers include, but are not limited to, thosedescribed in Hudecek et al. (2013) Clin. Cancer Res., 19:3153 orinternational patent application publication number WO2014031687. Insome embodiments, the spacer has the sequence set forth in SEQ IDNO:363, and is encoded by the sequence set forth in SEQ ID NO:364. Insome embodiments, the spacer has the sequence set forth in SEQ IDNO:365. In some embodiments, the spacer has the sequence set forth inSEQ ID NO:366.

The antigen-recognition component generally is linked to one or moreintracellular signaling components, such as signaling components thatmimic activation through an antigen receptor complex, such as a TCRcomplex, in the case of a CAR, and/or signal via another cell surfacereceptor. Thus, in some embodiments, the BCMA-binding molecule (e.g.,antibody or antigen binding fragment thereof) is linked to one or moretransmembrane domains such as those described herein and intracellularsignaling domains comprising one or more intracellular components suchas those described herein. In some embodiments, the transmembrane domainis fused to the extracellular domain. In one embodiment, a transmembranedomain that naturally is associated with one of the domains in thereceptor, e.g., CAR, is used. In some instances, the transmembranedomain is selected or modified by amino acid substitution to avoidbinding of such domains to the transmembrane domains of the same ordifferent surface membrane proteins to minimize interactions with othermembers of the receptor complex.

The transmembrane domain in some embodiments is derived either from anatural or from a synthetic source. Where the source is natural, thedomain in some aspects is derived from any membrane-bound ortransmembrane protein. Transmembrane domains include those derived from(i.e. comprise at least the transmembrane domain(s) of) the alpha, betaor zeta chain of the T-cell receptor, CD3 epsilon, CD4, CD5, CD8, CD9,CD16, CD22, CD28, CD33, CD37, CD45, CD64, CD80, CD86, CD134, CD137,and/or CD154. Alternatively the transmembrane domain in some embodimentsis synthetic. In some aspects, the synthetic transmembrane domaincomprises predominantly hydrophobic residues such as leucine and valine.In some aspects, a triplet of phenylalanine, tryptophan and valine willbe found at each end of a synthetic transmembrane domain. In someembodiments, the linkage is by linkers, spacers, and/or transmembranedomain(s).

Among the intracellular signaling domains are those that mimic orapproximate a signal through a natural antigen receptor, a signalthrough such a receptor in combination with a costimulatory receptor,and/or a signal through a costimulatory receptor alone. In someembodiments, a short oligo- or polypeptide linker, for example, a linkerof between 2 and 10 amino acids in length, such as one containingglycines and serines, e.g., glycine-serine doublet, is present and formsa linkage between the transmembrane domain and the intracellularsignaling domain of the CAR.

The receptor, e.g., the CAR, generally includes an intracellularsignaling domain comprising at least one intracellular signalingcomponent or components. In some embodiments, the receptor includes anintracellular component of a TCR complex, such as a TCR CD3 chain thatmediates T-cell activation and cytotoxicity, e.g., CD3 zeta chain. Thus,in some aspects, the BCMA-binding antibody is linked to one or more cellsignaling modules. In some embodiments, cell signaling modules includeCD3 transmembrane domain, CD3 intracellular signaling domains, and/orother CD transmembrane domains. In some embodiments, the receptor, e.g.,CAR, further includes a portion of one or more additional molecules suchas Fc receptor γ, CD8, CD4, CD25, or CD16. For example, in some aspects,the CAR includes a chimeric molecule between CD3-zeta (CD3-0 or Fcreceptor γ and CD8, CD4, CD25 or CD16.

In some embodiments, upon ligation of the CAR, the cytoplasmic domain orintracellular signaling domain of the CAR activates at least one of thenormal effector functions or responses of the immune cell, e.g., T cellengineered to express the CAR. For example, in some contexts, the CARinduces a function of a T cell such as cytolytic activity or T-helperactivity, such as secretion of cytokines or other factors. In someembodiments, a truncated portion of an intracellular signaling domain ofan antigen receptor component or costimulatory molecule is used in placeof an intact immunostimulatory chain, for example, if it transduces theeffector function signal. In some embodiments, the intracellularsignaling domain or domains include the cytoplasmic sequences of the Tcell receptor (TCR), and in some aspects also those of co-receptors thatin the natural context act in concert with such receptor to initiatesignal transduction following antigen receptor engagement, and/or anyderivative or variant of such molecules, and/or any synthetic sequencethat has the same functional capability.

In the context of a natural TCR, full activation generally requires notonly signaling through the TCR, but also a costimulatory signal. Thus,in some embodiments, to promote full activation, a component forgenerating secondary or co-stimulatory signal is also included in theCAR. In other embodiments, the CAR does not include a component forgenerating a costimulatory signal. In some aspects, an additional CAR isexpressed in the same cell and provides the component for generating thesecondary or costimulatory signal.

T cell activation is in some aspects described as being mediated by twoclasses of cytoplasmic signaling sequences: those that initiateantigen-dependent primary activation through the TCR (primarycytoplasmic signaling sequences), and those that act in anantigen-independent manner to provide a secondary or co-stimulatorysignal (secondary cytoplasmic signaling sequences). In some aspects, theCAR includes one or both of such classes of cytoplasmic signalingsequences.

In some aspects, the CAR includes a primary cytoplasmic signalingsequence that regulates primary activation of the TCR complex. Primarycytoplasmic signaling sequences that act in a stimulatory manner maycontain signaling motifs which are known as immunoreceptortyrosine-based activation motifs or ITAMs. Examples of ITAM containingprimary cytoplasmic signaling sequences include those derived from TCRor CD3 zeta, FcR gamma, CD3 gamma, CD3 delta and CD3 epsilon. In someembodiments, the intracellular signaling domain in the CAR contain(s) acytoplasmic signaling domain, portion thereof, or sequence derived fromCD3 zeta.

In some embodiments, the CAR includes a signaling domain (e.g., anintracellular signaling domain) and/or transmembrane portion of acostimulatory molecule, such as a T cell costimulatory molecule.Exemplary costimulatory molecules include CD28, 4-1BB, OX40, DAP10, andICOS. In some aspects, the same CAR includes both the activating orstimulatory components (e.g., cytoplasmic signaling sequence) andcostimulatory components.

In some embodiments, the activating or stimulatory components areincluded within one CAR, whereas the costimulatory component is providedby another CAR recognizing another antigen. In some embodiments, theCARs include activating or stimulatory CARs, and costimulatory CARs,both expressed on the same cell (see WO2014/055668). In some aspects,the BCMA-targeting CAR is the stimulatory or activating CAR; in otheraspects, it is the costimulatory CAR. In some embodiments, the cellsfurther include inhibitory CARs (iCARs, see Fedorov et al., Sci. Transl.Medicine, 5(215) (December, 2013), such as a CAR recognizing an antigenother than BCMA, whereby an activating or stimulatory signal deliveredthrough the BCMA-targeting CAR is diminished or inhibited by binding ofthe inhibitory CAR to its ligand, e.g., to reduce off-target effects.

In certain embodiments, the intracellular signaling domain comprises aCD28 transmembrane and signaling domain linked to a CD3 (e.g., CD3-zeta)intracellular domain. In some embodiments, the intracellular signalingdomain comprises a chimeric CD28 and CD137 (4-1BB, TNFRSF9)co-stimulatory domains, linked to a CD3 zeta intracellular domain.

In some embodiments, the CAR encompasses one or more, e.g., two or more,costimulatory domains and an activation domain, e.g., primary activationdomain, in the cytoplasmic portion. Exemplary CARs include intracellularcomponents of CD3-zeta, CD28, and 4-1BB.

In some embodiments, the nucleic acid sequences encoding a recombinantreceptor, e.g., CAR, further includes a nucleic acid sequence encodingone or more marker(s). In some embodiments, the one or more marker(s) isa transduction marker, surrogate marker and/or a selection marker.

In some embodiments, the marker is a transduction marker or a surrogatemarker. A transduction marker or a surrogate marker can be used todetect cells that have been introduced with the polynucleotide, e.g., apolynucleotide encoding a recombinant receptor. In some embodiments, thetransduction marker can indicate or confirm modification of a cell. Insome embodiments, the surrogate marker is a protein that is made to beco-expressed on the cell surface with the recombinant receptor, e.g.CAR. In particular embodiments, such a surrogate marker is a surfaceprotein that has been modified to have little or no activity. In certainembodiments, the surrogate marker is encoded on the same polynucleotidethat encodes the recombinant receptor. In some embodiments, the nucleicacid sequence encoding the recombinant receptor is operably linked to anucleic acid sequence encoding a marker, optionally separated by aninternal ribosome entry site (IRES), or a nucleic acid encoding aself-cleaving peptide or a peptide that causes ribosome skipping, suchas a 2A sequence, such as a T2A, a P2A, a E2A or a F2A. Extrinsic markergenes may in some cases be utilized in connection with engineered cellto permit detection or selection of cells and, in some cases, also topromote cell suicide.

Exemplary surrogate markers can include truncated cell surfacepolypeptides, such as a truncated human epidermal growth factor receptor2 (tHER2), a truncated epidermal growth factor receptor (EGFRt,exemplary EGFRt sequence set forth in SEQ ID NO:11 or 76) or aprostate-specific membrane antigen (PSMA) or modified form thereof.EGFRt may contain an epitope recognized by the antibody cetuximab(Erbitux®) or other therapeutic anti-EGFR antibody or binding molecule,which can be used to identify or select cells that have been engineeredwith the EGFRt construct and a recombinant receptor, such as a chimericantigen receptor (CAR), and/or to eliminate or separate cells expressingthe receptor. See U.S. Pat. No. 8,802,374 and Liu et al., NatureBiotech. 2016 April; 34(4): 430-434). In some aspects, the marker, e.g.surrogate marker, includes all or part (e.g., truncated form) of CD34, aNGFR, or epidermal growth factor receptor (e.g., tEGFR). In someembodiments, the nucleic acid encoding the marker is operably linked toa polynucleotide encoding for a linker sequence, such as a cleavablelinker sequence, e.g., T2A. For example, a marker, and optionally alinker sequence, can be any as disclosed in PCT Pub. No. WO2014031687.For example, the marker can be a truncated EGFR (tEGFR) that is,optionally, linked to a linker sequence, such as a T2A cleavable linkersequence. An exemplary polypeptide for a truncated EGFR (e.g. tEGFR)comprises the sequence of amino acids set forth in SEQ ID NO: 602 or 603or a sequence of amino acids that exhibits at least 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequenceidentity to SEQ ID NO: 602 or 603.

In some embodiments, the marker is or comprises a fluorescent protein,such as green fluorescent protein (GFP), enhanced green fluorescentprotein (EGFP), such as super-fold GFP, red fluorescent protein (RFP),such as tdTomato, mCherry, mStrawberry, AsRed2, DsRed or DsRed2, cyanfluorescent protein (CFP), blue green fluorescent protein (BFP),enhanced blue fluorescent protein (EBFP), and yellow fluorescent protein(YFP), and variants thereof, including species variants, monomericvariants, and codon-optimized and/or enhanced variants of thefluorescent proteins. In some embodiments, the marker is or comprises anenzyme, such as a luciferase, the lacZ gene from E. coli, alkalinephosphatase, secreted embryonic alkaline phosphatase (SEAP),chloramphenicol acetyl transferase (CAT). Exemplary light-emittingreporter genes include luciferase (luc), β-galactosidase,chloramphenicol acetyltransferase (CAT), β-glucuronidase (GUS) orvariants thereof.

In some embodiments, the marker is a selection marker. In someembodiments, the selection marker is or comprises a polypeptide thatconfers resistance to exogenous agents or drugs. In some embodiments,the selection marker is an antibiotic resistance gene. In someembodiments, the selection marker is an antibiotic resistance geneconfers antibiotic resistance to a mammalian cell. In some embodiments,the selection marker is or comprises a Puromycin resistance gene, aHygromycin resistance gene, a Blasticidin resistance gene, a Neomycinresistance gene, a Geneticin resistance gene or a Zeocin resistance geneor a modified form thereof.

In some embodiments, the marker is a molecule, e.g., cell surfaceprotein, not naturally found on T cells or not naturally found on thesurface of T cells, or a portion thereof.

In some embodiments, the molecule is a non-self molecule, e.g., non-selfprotein, i.e., one that is not recognized as “self” by the immune systemof the host into which the cells will be adoptively transferred.

In some embodiments, the marker serves no therapeutic function and/orproduces no effect other than to be used as a marker for geneticengineering, e.g., for selecting cells successfully engineered. In otherembodiments, the marker may be a therapeutic molecule or moleculeotherwise exerting some desired effect, such as a ligand for a cell tobe encountered in vivo, such as a costimulatory or immune checkpointmolecule to enhance and/or dampen responses of the cells upon adoptivetransfer and encounter with ligand.

In some cases, CARs are referred to as first, second, and/or thirdgeneration CARs. In some aspects, a first generation CAR is one thatsolely provides a CD3-chain induced signal upon antigen binding; in someaspects, a second-generation CARs is one that provides such a signal andcostimulatory signal, such as one including an intracellular signalingdomain from a costimulatory receptor such as CD28 or CD137; in someaspects, a third generation CAR in some aspects is one that includesmultiple costimulatory domains of different costimulatory receptors.

In some embodiments, the chimeric antigen receptor includes anextracellular portion containing the antibody or fragment describedherein. In some aspects, the chimeric antigen receptor includes anextracellular portion containing the antibody or fragment describedherein and an intracellular signaling domain. In some embodiments, theantibody or fragment includes an scFv or a single-domain antibodycomprising only the V_(H) region and the intracellular signaling domaincontains an ITAM. In some aspects, the intracellular signaling domainincludes a signaling domain of a zeta chain of a CD3-zeta (CD3) chain.In some embodiments, the chimeric antigen receptor includes atransmembrane domain linking the extracellular domain and theintracellular signaling domain. In some aspects, the transmembranedomain contains a transmembrane portion of CD28. The extracellulardomain and transmembrane can be linked directly or indirectly. In someembodiments, the extracellular domain and transmembrane are linked by aspacer, such as any described herein. In some embodiments, the chimericantigen receptor contains an intracellular domain of a co-stimulatorymolecule (e.g., T cell costimulatory molecule), such as between thetransmembrane domain and intracellular signaling domain. In someaspects, the T cell costimulatory molecule is CD28 or 4-1BB.

In some embodiments, the transmembrane domain of the receptor (e.g.,CAR) is a transmembrane domain of human CD28 or variant thereof, e.g., a27-amino acid transmembrane domain of a human CD28 (Accession No.:P10747.1). In some embodiments, the intracellular signaling domaincomprises an intracellular costimulatory signaling domain of human CD28or functional variant thereof, such as a 41 amino acid domain thereofand/or such a domain with an LL to GG substitution at positions 186-187of a native CD28 protein. In some embodiments, the intracellular domaincomprises an intracellular costimulatory signaling domain of 4-1BB orfunctional variant thereof, such as a 42-amino acid cytoplasmic domainof a human 4-1BB (Accession No. Q07011.1). In some embodiments, theintracellular signaling domain comprises a human CD3 zeta stimulatorysignaling domain or functional variant thereof, such as an 112 AAcytoplasmic domain of isoform 3 of human CD3 (Accession No.: P20963.2)or a CD3 zeta signaling domain as described in U.S. Pat. No. 7,446,190.

In some aspects, the spacer contains only a hinge region of an IgG, suchas only a hinge of IgG4 or IgG1, such as the hinge only spacer set forthin SEQ ID NO:363. In other embodiments, the spacer is an Ig hinge, e.g.,and IgG4 hinge, linked to a CH2 and/or CH3 domains. In some embodiments,the spacer is an Ig hinge, e.g., an IgG4 hinge, linked to CH2 and CH3domains, such as set forth in SEQ ID NO:366. In some embodiments, thespacer is an Ig hinge, e.g., an IgG4 hinge, linked to a CH3 domain only,such as set forth in SEQ ID NO:365. In some embodiments, the spacer isor comprises a glycine-serine rich sequence or other flexible linkersuch as known flexible linkers.

For example, in some embodiments, the CAR includes a BCMA antibody orfragment, such as any of the human BCMA antibodies, including sdAbs andscFvs, described herein, a spacer such as any of the Ig-hinge containingspacers, a CD28 transmembrane domain, a CD28 intracellular signalingdomain, and a CD3 zeta signaling domain. In some embodiments, the CARincludes the BCMA antibody or fragment, such as any of the human BCMAantibodies, including sdAbs and scFvs described herein, a spacer such asany of the Ig-hinge containing spacers, a CD28 transmembrane domain, a4-1BB intracellular signaling domain, and a CD3 zeta signaling domain.In some embodiments, such CAR constructs further includes a T2Aribosomal skip element and/or a tEGFR sequence, e.g., downstream of theCAR.

In certain embodiments, multispecific binding molecules, e.g.,multispecific chimeric receptors, such as multispecific CARs, cancontain any of the multispecific antibodies, including, e.g. bispecificantibodies, multispecific single-chain antibodies, e.g., diabodies,triabodies, and tetrabodies, tandem di-scFvs, and tandem tri-scFvs, suchas any described above in Section I.A.

Also provided herein are single chain cell surface proteins comprisingthe scFv sequence selected from any of SEQ ID NOs:128-139, 268-278,558-576 and 578-583. In some of any such embodiments, the scFv comprisesthe sequence selected from any of SEQ ID NOs:128, 132, 278 and 502. Insome of any such embodiments, the scFv comprises the sequence of SEQ IDNO:560.

C. Engineered Cells

Also provided are cells such as engineered cells that contain arecombinant receptor (e.g., a chimeric antigen receptor) such as onethat contains an extracellular domain including an anti-BCMA antibody orfragment as described herein. Also provided are populations of suchcells, compositions containing such cells and/or enriched for suchcells, such as in which cells expressing the BCMA-binding molecule makeup at least 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, ormore percent of the total cells in the composition or cells of a certaintype such as T cells or CD8+ or CD4+ cells. Among the compositions arepharmaceutical compositions and formulations for administration, such asfor adoptive cell therapy. Also provided are therapeutic methods foradministering the cells and compositions to subjects, e.g., patients.

Thus also provided are genetically engineered cells expressing therecombinant receptors containing the antibodies, e.g., cells containingthe CARs. The cells generally are eukaryotic cells, such as mammaliancells, and typically are human cells. In some embodiments, the cells arederived from the blood, bone marrow, lymph, or lymphoid organs, arecells of the immune system, such as cells of the innate or adaptiveimmunity, e.g., myeloid or lymphoid cells, including lymphocytes,typically T cells and/or NK cells. Other exemplary cells include stemcells, such as multipotent and pluripotent stem cells, including inducedpluripotent stem cells (iPSCs). The cells typically are primary cells,such as those isolated directly from a subject and/or isolated from asubject and frozen. In some embodiments, the cells include one or moresubsets of T cells or other cell types, such as whole T cellpopulations, CD4+ cells, CD8+ cells, and subpopulations thereof, such asthose defined by function, activation state, maturity, potential fordifferentiation, expansion, recirculation, localization, and/orpersistence capacities, antigen-specificity, type of antigen receptor,presence in a particular organ or compartment, marker or cytokinesecretion profile, and/or degree of differentiation. With reference tothe subject to be treated, the cells may be allogeneic and/orautologous. Among the methods include off-the-shelf methods. In someaspects, such as for off-the-shelf technologies, the cells arepluripotent and/or multipotent, such as stem cells, such as inducedpluripotent stem cells (iPSCs). In some embodiments, the methods includeisolating cells from the subject, preparing, processing, culturing,and/or engineering them, as described herein, and re-introducing theminto the same patient, before or after cryopreservation.

Among the sub-types and subpopulations of T cells and/or of CD4+ and/orof CD8+ T cells are naïve T (T_(N)) cells, effector T cells (T_(EFF)),memory T cells and sub-types thereof, such as stem cell memory T(T_(SCM)), central memory T (T_(CM)), effector memory T (T_(EM)), orterminally differentiated effector memory T cells, tumor-infiltratinglymphocytes (TIL), immature T cells, mature T cells, helper T cells,cytotoxic T cells, mucosa-associated invariant T (MATT) cells, naturallyoccurring and adaptive regulatory T (Treg) cells, helper T cells, suchas TH1 cells, TH2 cells, TH3 cells, TH17 cells, TH9 cells, TH22 cells,follicular helper T cells, alpha/beta T cells, and delta/gamma T cells.

In some embodiments, the cells are natural killer (NK) cells. In someembodiments, the cells are monocytes or granulocytes, e.g., myeloidcells, macrophages, neutrophils, dendritic cells, mast cells,eosinophils, and/or basophils.

In some embodiments, the cells include one or more nucleic acidsintroduced via genetic engineering, and thereby express recombinant orgenetically engineered products of such nucleic acids. In someembodiments, the nucleic acids are heterologous, i.e., normally notpresent in a cell or sample obtained from the cell, such as one obtainedfrom another organism or cell, which for example, is not ordinarilyfound in the cell being engineered and/or an organism from which suchcell is derived. In some embodiments, the nucleic acids are notnaturally occurring, such as a nucleic acid not found in nature,including one comprising chimeric combinations of nucleic acids encodingvarious domains from multiple different cell types. In some embodiments,the cells (e.g., engineered cells) comprise a vector (e.g., a viralvector, expression vector, etc.) as described herein such as a vectorcomprising a nucleic acid encoding a recombinant receptor describedherein.

a. Vectors and Methods for Genetic Engineering

Also provided are methods, nucleic acids, compositions, and kits, forexpressing the binding molecules (e.g., anti-BCMA binding molecules),including recombinant receptors (e.g., CARs) comprising the bindingmolecules, and for producing the genetically engineered cells expressingsuch binding molecules. In some embodiments, one or more bindingmolecules, including recombinant receptors (e.g., CARs) can begenetically engineered into cells or plurality of cells. The geneticengineering generally involves introduction of a nucleic acid encodingthe recombinant or engineered component into the cell, such as byretroviral transduction, transfection, or transformation.

In some embodiments, gene transfer is accomplished by first stimulatingthe cell, such as by combining it with a stimulus that induces aresponse such as proliferation, survival, and/or activation, e.g., asmeasured by expression of a cytokine or activation marker, followed bytransduction of the activated cells, and expansion in culture to numberssufficient for clinical applications.

In some contexts, overexpression of a stimulatory factor (for example, alymphokine or a cytokine) may be toxic to a subject. Thus, in somecontexts, the engineered cells include gene segments that cause thecells to be susceptible to negative selection in vivo, such as uponadministration in adoptive immunotherapy. For example in some aspects,the cells are engineered so that they can be eliminated as a result of achange in the in vivo condition of the patient to which they areadministered. The negative selectable phenotype may result from theinsertion of a gene that confers sensitivity to an administered agent,for example, a compound. Negative selectable genes include the Herpessimplex virus type I thymidine kinase (HSV-I TK) gene (Wigler et al.,Cell 2:223, 1977) which confers ganciclovir sensitivity; the cellularhypoxanthine phosphoribosyltransferase (HPRT) gene, the cellular adeninephosphoribosyltransferase (APRT) gene, bacterial cytosine deaminase,(Mullen et al., Proc. Natl. Acad. Sci. USA. 89:33 (1992)).

In some aspects, the cells further are engineered to promote expressionof cytokines or other factors. Various methods for the introduction ofgenetically engineered components, e.g., antigen receptors, e.g., CARs,are well known and may be used with the provided methods andcompositions. Exemplary methods include those for transfer of nucleicacids encoding the receptors, including via viral, e.g., retroviral orlentiviral, transduction, transposons, and electroporation.

In some embodiments, recombinant nucleic acids are transferred intocells using recombinant infectious virus particles, such as, e.g.,vectors derived from simian virus 40 (SV40), adenoviruses,adeno-associated virus (AAV). In some embodiments, recombinant nucleicacids are transferred into T cells using recombinant lentiviral vectorsor retroviral vectors, such as gamma-retroviral vectors (see, e.g.,Koste et al. (2014) Gene Therapy 2014 Apr. 3. doi: 10.1038/gt.2014.25;Carlens et al. (2000) Exp Hematol 28(10): 1137-46; Alonso-Camino et al.(2013) Mol Ther Nucl Acids 2, e93; Park et al., Trends Biotechnol. 2011November 29(11): 550-557).

In some embodiments, the retroviral vector has a long terminal repeatsequence (LTR), e.g., a retroviral vector derived from the Moloneymurine leukemia virus (MoMLV), myeloproliferative sarcoma virus (MPSV),murine embryonic stem cell virus (MESV), murine stem cell virus (MSCV),spleen focus forming virus (SFFV), human immunodeficiency virus type 1(HIV-1) or adeno-associated virus (AAV). Most retroviral vectors arederived from murine retroviruses. In some embodiments, the retrovirusesinclude those derived from any avian or mammalian cell source. Theretroviruses typically are amphotropic, meaning that they are capable ofinfecting host cells of several species, including humans. In oneembodiment, the gene to be expressed replaces the retroviral gag, poland/or env sequences. A number of illustrative retroviral systems havebeen described (e.g., U.S. Pat. Nos. 5,219,740; 6,207,453; 5,219,740;Miller and Rosman (1989) BioTechniques 7:980-990; Miller, A. D. (1990)Human Gene Therapy 1:5-14; Scarpa et al. (1991) Virology 180:849-852;Burns et al. (1993) Proc. Natl. Acad. Sci. USA 90:8033-8037; andBoris-Lawrie and Temin (1993) Cur. Opin. Genet. Develop. 3:102-109.

Methods of lentiviral transduction are known. Exemplary methods aredescribed in, e.g., Wang et al. (2012) J. Immunother. 35(9): 689-701;Cooper et al. (2003) Blood. 101:1637-1644; Verhoeyen et al. (2009)Methods Mol Biol. 506: 97-114; and Cavalieri et al. (2003) Blood.102(2): 497-505.

In some embodiments, recombinant nucleic acids are transferred into Tcells via electroporation (see, e.g., Chicaybam et al, (2013) PLoS ONE8(3): e60298 and Van Tedeloo et al. (2000) Gene Therapy 7(16):1431-1437). In some embodiments, recombinant nucleic acids aretransferred into T cells via transposition (see, e.g., Manuri et al.(2010) Hum Gene Ther 21(4): 427-437; Sharma et al. (2013) Molec TherNucl Acids 2, e74; and Huang et al. (2009) Methods Mol Biol 506:115-126). Other methods of introducing and expressing genetic materialin immune cells include calcium phosphate transfection (e.g., asdescribed in Current Protocols in Molecular Biology, John Wiley & Sons,New York. N.Y.), protoplast fusion, cationic liposome-mediatedtransfection; tungsten particle-facilitated microparticle bombardment(Johnston, Nature, 346: 776-777 (1990)); and strontium phosphate DNAco-precipitation (Brash et al., Mol. Cell Biol., 7: 2031-2034 (1987)).

Other approaches and vectors for transfer of the nucleic acids encodingthe recombinant products are those described, e.g., in internationalpatent application, Publication No.: WO2014055668, and U.S. Pat. No.7,446,190.

Among additional nucleic acids, e.g., genes for introduction are thoseto improve the efficacy of therapy, such as by promoting viabilityand/or function of transferred cells; genes to provide a genetic markerfor selection and/or evaluation of the cells, such as to assess in vivosurvival or localization; genes to improve safety, for example, bymaking the cell susceptible to negative selection in vivo as describedby Lupton S. D. et al., Mol. and Cell Biol., 11:6 (1991); and Riddell etal., Human Gene Therapy 3:319-338 (1992); see also the publications ofPCT/US91/08442 and PCT/US94/05601 by Lupton et al. describing the use ofbifunctional selectable fusion genes derived from fusing a dominantpositive selectable marker with a negative selectable marker. See, e.g.,Riddell et al., U.S. Pat. No. 6,040,177, at columns 14-17.

In some embodiments, one or more binding molecules, including antibodiesand/or recombinant receptors (e.g., CARs), can be genetically engineeredto be expressed in cells or plurality of cells. In some embodiments, afirst recombinant receptor and a second binding molecule, e.g.,recombinant receptor, are encoded by the same or separate nucleic acidmolecules. In some embodiments, additional binding molecules areengineered to be expressed in cells or a plurality of cells.

In some embodiments, the vector or construct can contain a singlepromoter that drives the expression of one or more nucleic acidmolecules. In some embodiments, such nucleic acid molecules, e.g.,transcripts, can be multicistronic (bicistronic or tricistronic, seee.g., U.S. Pat. No. 6,060,273). For example, in some embodiments,transcription units can be engineered as a bicistronic unit containingan IRES (internal ribosome entry site), which allows coexpression ofgene products (e.g. encoding a first and second chimeric receptor) by amessage from a single promoter. Alternatively, in some cases, a singlepromoter may direct expression of an RNA that contains, in a single openreading frame (ORF), two or three genes (e.g. encoding the moleculeinvolved in modulating a metabolic pathway and encoding the recombinantreceptor) separated from one another by sequences encoding aself-cleavage peptide (e.g., 2A sequences) or a protease recognitionsite (e.g., furin). The ORF thus encodes a single polypeptide, which,either during (in the case of 2A) or after translation, is processedinto the individual proteins. In some cases, the peptide, such as T2A,can cause the ribosome to skip (ribosome skipping) synthesis of apeptide bond at the C-terminus of a 2A element, leading to separationbetween the end of the 2A sequence and the next peptide downstream (see,for example, de Felipe. Genetic Vaccines and Ther. 2:13 (2004) anddeFelipe et al. Traffic 5:616-626 (2004)). Many 2A elements are known inthe art. Examples of 2A sequences that can be used in the methods andnucleic acids disclosed herein, without limitation, 2A sequences fromthe foot-and-mouth disease virus (F2A, e.g., SEQ ID NO: 601), equinerhinitis A virus (E2A, e.g., SEQ ID NO: 600), Thosea asigna virus (T2A,e.g., SEQ ID NO: 596 or 597), and porcine teschovirus-1 (P2A, e.g., SEQID NO: 598 or 599) as described in U.S. Patent Publication No.20070116690. In some embodiments, the one or more different or separatepromoters drive the expression of one or more nucleic acid moleculesencoding the one or more binding molecules, e.g., recombinant receptors.

Any of the binding molecules, e.g., antibodies and/or recombinantreceptors provided herein, e.g., BCMA-binding molecules and/or theadditional recombinant receptors, can be encoded by polynucleotidescontaining one or more nucleic acid molecules encoding the receptors, inany combinations or arrangements. For example, one, two, three or morepolynucleotides can encode one, two, three or more different receptorsor domains. In some embodiments, one vector or construct containsnucleic acid molecules encoding one or more binding molecules, e.g.,antibody and/or recombinant receptor, and a separate vector or constructcontains nucleic acid molecules encoding an additional binding molecule,e.g., antibody and/or recombinant receptor. Each of the nucleic acidmolecule can also encode one or more marker, such as a surface marker,e.g., truncated EGFR (tEGFR).

Also provided are compositions containing one or more of the nucleicacid molecules, vectors or constructs, such as any described above. Insome embodiments, the nucleic acid molecules, vectors, constructs orcompositions can be used to engineer cells, such as T cells, to expressany of the binding molecules, e.g., antibody or recombinant receptor,and/or the additional binding molecules.

b. Preparation of Cells for Engineering

In some embodiments, preparation of the engineered cells includes one ormore culture and/or preparation steps. The cells for introduction of therecombinant receptor (e.g., CAR) may be isolated from a sample, such asa biological sample, e.g., one obtained from or derived from a subject.In some embodiments, the subject from which the cell is isolated is onehaving the disease or condition or in need of a cell therapy or to whichcell therapy will be administered. The subject in some embodiments is ahuman in need of a particular therapeutic intervention, such as theadoptive cell therapy for which cells are being isolated, processed,and/or engineered.

Accordingly, the cells in some embodiments are primary cells, e.g.,primary human cells. The samples include tissue, fluid, and othersamples taken directly from the subject, as well as samples resultingfrom one or more processing steps, such as separation, centrifugation,genetic engineering (e.g. transduction with viral vector), washing,and/or incubation. The biological sample can be a sample obtaineddirectly from a biological source or a sample that is processed.Biological samples include, but are not limited to, body fluids, such asblood, plasma, serum, cerebrospinal fluid, synovial fluid, urine andsweat, tissue and organ samples, including processed samples derivedtherefrom.

In some aspects, the sample from which the cells are derived or isolatedis blood or a blood-derived sample, or is or is derived from anapheresis or leukapheresis product. Exemplary samples include wholeblood, peripheral blood mononuclear cells (PBMCs), leukocytes, bonemarrow, thymus, tissue biopsy, tumor, leukemia, lymphoma, lymph node,gut associated lymphoid tissue, mucosa associated lymphoid tissue,spleen, other lymphoid tissues, liver, lung, stomach, intestine, colon,kidney, pancreas, breast, bone, prostate, cervix, testes, ovaries,tonsil, or other organ, and/or cells derived therefrom. Samples include,in the context of cell therapy, e.g., adoptive cell therapy, samplesfrom autologous and allogeneic sources.

In some embodiments, the cells are derived from cell lines, e.g., T celllines. The cells in some embodiments are obtained from a xenogeneicsource, for example, from mouse, rat, non-human primate, or pig.

In some embodiments, isolation of the cells includes one or morepreparation and/or non-affinity based cell separation steps. In someexamples, cells are washed, centrifuged, and/or incubated in thepresence of one or more reagents, for example, to remove unwantedcomponents, enrich for desired components, lyse or remove cellssensitive to particular reagents. In some examples, cells are separatedbased on one or more property, such as density, adherent properties,size, sensitivity and/or resistance to particular components.

In some examples, cells from the circulating blood of a subject areobtained, e.g., by apheresis or leukapheresis. The samples, in someaspects, contain lymphocytes, including T cells, monocytes,granulocytes, B cells, other nucleated white blood cells, red bloodcells, and/or platelets, and in some aspects contain cells other thanred blood cells and platelets.

In some embodiments, the blood cells collected from the subject arewashed, e.g., to remove the plasma fraction and to place the cells in anappropriate buffer or media for subsequent processing steps. In someembodiments, the cells are washed with phosphate buffered saline (PBS).In some embodiments, the wash solution lacks calcium and/or magnesiumand/or many or all divalent cations. In some aspects, a washing step isaccomplished a semi-automated “flow-through” centrifuge (for example,the Cobe 2991 cell processor, Baxter) according to the manufacturer'sinstructions. In some aspects, a washing step is accomplished bytangential flow filtration (TFF) according to the manufacturer'sinstructions. In some embodiments, the cells are resuspended in avariety of biocompatible buffers after washing, such as, for example,Ca⁺⁺/Mg⁺⁺ free PBS. In certain embodiments, components of a blood cellsample are removed and the cells directly resuspended in culture media.

In some embodiments, the methods include density-based cell separationmethods, such as the preparation of white blood cells from peripheralblood by lysing the red blood cells and centrifugation through a Percollor Ficoll gradient.

In some embodiments, the isolation methods include the separation ofdifferent cell types based on the expression or presence in the cell ofone or more specific molecules, such as surface markers, e.g., surfaceproteins, intracellular markers, or nucleic acid. In some embodiments,any known method for separation based on such markers may be used. Insome embodiments, the separation is affinity- or immunoaffinity-basedseparation. For example, the isolation in some aspects includesseparation of cells and cell populations based on the cells' expressionor expression level of one or more markers, typically cell surfacemarkers, for example, by incubation with an antibody or binding partnerthat specifically binds to such markers, followed generally by washingsteps and separation of cells having bound the antibody or bindingpartner, from those cells having not bound to the antibody or bindingpartner.

Such separation steps can be based on positive selection, in which thecells having bound the reagents are retained for further use, and/ornegative selection, in which the cells having not bound to the antibodyor binding partner are retained. In some examples, both fractions areretained for further use. In some aspects, negative selection can beparticularly useful where no antibody is available that specificallyidentifies a cell type in a heterogeneous population, such thatseparation is best carried out based on markers expressed by cells otherthan the desired population.

The separation need not result in 100% enrichment or removal of aparticular cell population or cells expressing a particular marker. Forexample, positive selection of or enrichment for cells of a particulartype, such as those expressing a marker, refers to increasing the numberor percentage of such cells, but need not result in a complete absenceof cells not expressing the marker. Likewise, negative selection,removal, or depletion of cells of a particular type, such as thoseexpressing a marker, refers to decreasing the number or percentage ofsuch cells, but need not result in a complete removal of all such cells.

In some examples, multiple rounds of separation steps are carried out,where the positively or negatively selected fraction from one step issubjected to another separation step, such as a subsequent positive ornegative selection. In some examples, a single separation step candeplete cells expressing multiple markers simultaneously, such as byincubating cells with a plurality of antibodies or binding partners,each specific for a marker targeted for negative selection. Likewise,multiple cell types can simultaneously be positively selected byincubating cells with a plurality of antibodies or binding partnersexpressed on the various cell types.

For example, in some aspects, specific subpopulations of T cells, suchas cells positive or expressing high levels of one or more surfacemarkers, e.g., CD28+, CD62L+, CCR7+, CD27+, CD127+, CD4+, CD8+, CD45RA+,and/or CD45RO+ T cells, are isolated by positive or negative selectiontechniques.

For example, CD3+, CD28+ T cells can be positively selected usinganti-CD3/anti-CD28 conjugated magnetic beads (e.g., DYNABEADS® M-450CD3/CD28 T Cell Expander, MACSiBeads, etc.).

In some embodiments, isolation is carried out by enrichment for aparticular cell population by positive selection, or depletion of aparticular cell population, by negative selection. In some embodiments,positive or negative selection is accomplished by incubating cells withone or more antibodies or other binding agent that specifically bind toone or more surface markers expressed or expressed (marker⁺) at arelatively higher level (marker^(high)) on the positively or negativelyselected cells, respectively.

In some embodiments, T cells are separated from a PBMC sample bynegative selection of markers expressed on non-T cells, such as B cells,monocytes, or other white blood cells, such as CD14. In some aspects, aCD4+ or CD8+ selection step is used to separate CD4+ helper and CD8+cytotoxic T cells. Such CD4+ and CD8+ populations can be further sortedinto sub-populations by positive or negative selection for markersexpressed or expressed to a relatively higher degree on one or morenaive, memory, and/or effector T cell subpopulations.

In some embodiments, CD8+ cells are further enriched for or depleted ofnaive, central memory, effector memory, and/or central memory stemcells, such as by positive or negative selection based on surfaceantigens associated with the respective subpopulation. In someembodiments, enrichment for central memory T (T_(CM)) cells is carriedout to increase efficacy, such as to improve long-term survival,expansion, and/or engraftment following administration, which in someaspects is particularly robust in such sub-populations. See Terakura etal. (2012) Blood. 1:72-82; Wang et al. (2012) J Immunother.35(9):689-701. In some embodiments, combining T_(CM)-enriched CD8+ Tcells and CD4+ T cells further enhances efficacy.

In embodiments, memory T cells are present in both CD62L+ and CD62L−subsets of CD8+ peripheral blood lymphocytes. PBMC can be enriched foror depleted of CD62L-CD8+ and/or CD62L+CD8+ fractions, such as usinganti-CD8 and anti-CD62L antibodies.

In some embodiments, the enrichment for central memory T (T_(CM)) cellsis based on positive or high surface expression of CD45RO, CD62L, CCR7,CD28, CD3, and/or CD 127; in some aspects, it is based on negativeselection for cells expressing or highly expressing CD45RA and/orgranzyme B. In some aspects, isolation of a CD8+ population enriched forT_(CM) cells is carried out by depletion of cells expressing CD4, CD14,CD45RA, and positive selection or enrichment for cells expressing CD62L.In one aspect, enrichment for central memory T (T_(CM)) cells is carriedout starting with a negative fraction of cells selected based on CD4expression, which is subjected to a negative selection based onexpression of CD14 and CD45RA, and a positive selection based on CD62L.Such selections in some aspects are carried out simultaneously and inother aspects are carried out sequentially, in either order. In someaspects, the same CD4 expression-based selection step used in preparingthe CD8+ cell population or subpopulation, also is used to generate theCD4+ cell population or subpopulation, such that both the positive andnegative fractions from the CD4-based separation are retained and usedin subsequent steps of the methods, optionally following one or morefurther positive or negative selection steps.

In a particular example, a sample of PBMCs or other white blood cellsample is subjected to selection of CD4+ cells, where both the negativeand positive fractions are retained. The negative fraction then issubjected to negative selection based on expression of CD14 and CD45RA,and positive selection based on a marker characteristic of centralmemory T cells, such as CD62L or CCR7, where the positive and negativeselections are carried out in either order.

CD4+T helper cells are sorted into naïve, central memory, and effectorcells by identifying cell populations that have cell surface antigens.CD4+ lymphocytes can be obtained by standard methods. In someembodiments, naive CD4+T lymphocytes are CD45RO−, CD45RA+, CD62L+, CD4+T cells. In some embodiments, central memory CD4+ cells are CD62L+ andCD45RO+. In some embodiments, effector CD4+ cells are CD62L- and CD45RO−

In one example, to enrich for CD4+ cells by negative selection, amonoclonal antibody cocktail typically includes antibodies to CD14,CD20, CD11b, CD16, HLA-DR, and CD8. In some embodiments, the antibody orbinding partner is bound to a solid support or matrix, such as amagnetic bead or paramagnetic bead, to allow for separation of cells forpositive and/or negative selection. For example, in some embodiments,the cells and cell populations are separated or isolated usingimmunomagnetic (or affinitymagnetic) separation techniques (reviewed inMethods in Molecular Medicine, vol. 58: Metastasis Research Protocols,Vol. 2: Cell Behavior In vitro and In vivo, p 17-25 Edited by: S. A.Brooks and U. Schumacher © Humana Press Inc., Totowa, NJ).

In some aspects, the sample or composition of cells to be separated isincubated with small, magnetizable or magnetically responsive material,such as magnetically responsive particles or microparticles, such asparamagnetic beads (e.g., such as Dynabeads or MACS beads). Themagnetically responsive material, e.g., particle, generally is directlyor indirectly attached to a binding partner, e.g., an antibody, thatspecifically binds to a molecule, e.g., surface marker, present on thecell, cells, or population of cells that it is desired to separate,e.g., that it is desired to negatively or positively select.

In some embodiments, the magnetic particle or bead comprises amagnetically responsive material bound to a specific binding member,such as an antibody or other binding partner. There are many well-knownmagnetically responsive materials used in magnetic separation methods.Suitable magnetic particles include those described in Molday, U.S. Pat.No. 4,452,773, and in European Patent Specification EP 452342 B, whichare hereby incorporated by reference. Colloidal sized particles, such asthose described in Owen U.S. Pat. No. 4,795,698, and Liberti et al.,U.S. Pat. No. 5,200,084, are other examples.

The incubation generally is carried out under conditions whereby theantibodies or binding partners, or molecules, such as secondaryantibodies or other reagents, which specifically bind to such antibodiesor binding partners, which are attached to the magnetic particle orbead, specifically bind to cell surface molecules if present on cellswithin the sample.

In some aspects, the sample is placed in a magnetic field, and thosecells having magnetically responsive or magnetizable particles attachedthereto will be attracted to the magnet and separated from the unlabeledcells. For positive selection, cells that are attracted to the magnetare retained; for negative selection, cells that are not attracted(unlabeled cells) are retained. In some aspects, a combination ofpositive and negative selection is performed during the same selectionstep, where the positive and negative fractions are retained and furtherprocessed or subject to further separation steps.

In certain embodiments, the magnetically responsive particles are coatedin primary antibodies or other binding partners, secondary antibodies,lectins, enzymes, or streptavidin. In certain embodiments, the magneticparticles are attached to cells via a coating of primary antibodiesspecific for one or more markers. In certain embodiments, the cells,rather than the beads, are labeled with a primary antibody or bindingpartner, and then cell-type specific secondary antibody- or otherbinding partner (e.g., streptavidin)-coated magnetic particles, areadded. In certain embodiments, streptavidin-coated magnetic particlesare used in conjunction with biotinylated primary or secondaryantibodies.

In some embodiments, the magnetically responsive particles are leftattached to the cells that are to be subsequently incubated, culturedand/or engineered; in some aspects, the particles are left attached tothe cells for administration to a patient. In some embodiments, themagnetizable or magnetically responsive particles are removed from thecells. Methods for removing magnetizable particles from cells are knownand include, e.g., the use of competing non-labeled antibodies,magnetizable particles or antibodies conjugated to cleavable linkers,etc. In some embodiments, the magnetizable particles are biodegradable.

In some embodiments, the affinity-based selection is viamagnetic-activated cell sorting (MACS) (Miltenyi Biotec, Auburn, CA).Magnetic Activated Cell Sorting (MACS) systems are capable ofhigh-purity selection of cells having magnetized particles attachedthereto. In certain embodiments, MACS operates in a mode wherein thenon-target and target species are sequentially eluted after theapplication of the external magnetic field. That is, the cells attachedto magnetized particles are held in place while the unattached speciesare eluted. Then, after this first elution step is completed, thespecies that were trapped in the magnetic field and were prevented frombeing eluted are freed in some manner such that they can be eluted andrecovered. In certain embodiments, the non-target cells are labelled anddepleted from the heterogeneous population of cells.

In certain embodiments, the isolation or separation is carried out usinga system, device, or apparatus that carries out one or more of theisolation, cell preparation, separation, processing, incubation,culture, and/or formulation steps of the methods. In some aspects, thesystem is used to carry out each of these steps in a closed or sterileenvironment, for example, to minimize error, user handling and/orcontamination. In one example, the system is a system as described inInternational Patent Application, Publication Number WO2009/072003, orUS 20110003380 A1.

In some embodiments, the system or apparatus carries out one or more,e.g., all, of the isolation, processing, engineering, and formulationsteps in an integrated or self-contained system, and/or in an automatedor programmable fashion. In some aspects, the system or apparatusincludes a computer and/or computer program in communication with thesystem or apparatus, which allows a user to program, control, assess theoutcome of, and/or adjust various aspects of the processing, isolation,engineering, and formulation steps.

In some aspects, the separation and/or other steps is carried out usingCliniMACS system (Miltenyi Biotec), for example, for automatedseparation of cells on a clinical-scale level in a closed and sterilesystem. Components can include an integrated microcomputer, magneticseparation unit, peristaltic pump, and various pinch valves. Theintegrated computer in some aspects controls all components of theinstrument and directs the system to perform repeated procedures in astandardized sequence. The magnetic separation unit in some aspectsincludes a movable permanent magnet and a holder for the selectioncolumn. The peristaltic pump controls the flow rate throughout thetubing set and, together with the pinch valves, ensures the controlledflow of buffer through the system and continual suspension of cells.

The CliniMACS system in some aspects uses antibody-coupled magnetizableparticles that are supplied in a sterile, non-pyrogenic solution. Insome embodiments, after labelling of cells with magnetic particles thecells are washed to remove excess particles. A cell preparation bag isthen connected to the tubing set, which in turn is connected to a bagcontaining buffer and a cell collection bag. The tubing set consists ofpre-assembled sterile tubing, including a pre-column and a separationcolumn, and are for single use only. After initiation of the separationprogram, the system automatically applies the cell sample onto theseparation column. Labelled cells are retained within the column, whileunlabeled cells are removed by a series of washing steps. In someembodiments, the cell populations for use with the methods describedherein are unlabeled and are not retained in the column. In someembodiments, the cell populations for use with the methods describedherein are labeled and are retained in the column. In some embodiments,the cell populations for use with the methods described herein areeluted from the column after removal of the magnetic field, and arecollected within the cell collection bag.

In certain embodiments, separation and/or other steps are carried outusing the CliniMACS Prodigy system (Miltenyi Biotec). The CliniMACSProdigy system in some aspects is equipped with a cell processing unitythat permits automated washing and fractionation of cells bycentrifugation. The CliniMACS Prodigy system can also include an onboardcamera and image recognition software that determines the optimal cellfractionation endpoint by discerning the macroscopic layers of thesource cell product. For example, peripheral blood may be automaticallyseparated into erythrocytes, white blood cells and plasma layers. TheCliniMACS Prodigy system can also include an integrated cell cultivationchamber which accomplishes cell culture protocols such as, e.g., celldifferentiation and expansion, antigen loading, and long-term cellculture. Input ports can allow for the sterile removal and replenishmentof media and cells can be monitored using an integrated microscope. See,e.g., Klebanoff et al. (2012) J Immunother. 35(9): 651-660, Terakura etal. (2012) Blood. 1:72-82, and Wang et al. (2012) J Immunother.35(9):689-701.

In some embodiments, a cell population described herein is collected andenriched (or depleted) via flow cytometry, in which cells stained formultiple cell surface markers are carried in a fluidic stream. In someembodiments, a cell population described herein is collected andenriched (or depleted) via preparative scale (FACS)-sorting. In certainembodiments, a cell population described herein is collected andenriched (or depleted) by use of microelectromechanical systems (MEMS)chips in combination with a FACS-based detection system (see, e.g., WO2010/033140, Cho et al. (2010) Lab Chip 10, 1567-1573; and Godin et al.(2008) J Biophoton. 1(5):355-376. In both cases, cells can be labeledwith multiple markers, allowing for the isolation of well-defined T cellsubsets at high purity.

In some embodiments, the antibodies or binding partners are labeled withone or more detectable marker, to facilitate separation for positiveand/or negative selection. For example, separation may be based onbinding to fluorescently labeled antibodies. In some examples,separation of cells based on binding of antibodies or other bindingpartners specific for one or more cell surface markers are carried in afluidic stream, such as by fluorescence-activated cell sorting (FACS),including preparative scale (FACS) and/or microelectromechanical systems(MEMS) chips, e.g., in combination with a flow-cytometric detectionsystem. Such methods allow for positive and negative selection based onmultiple markers simultaneously.

In some embodiments, the preparation methods include steps for freezing,e.g., cryopreserving, the cells, either before or after isolation,incubation, and/or engineering. In some embodiments, the freeze andsubsequent thaw step removes granulocytes and, to some extent, monocytesin the cell population. In some embodiments, the cells are suspended ina freezing solution, e.g., following a washing step to remove plasma andplatelets. Any of a variety of known freezing solutions and parametersin some aspects may be used. One example involves using PBS containing20% DMSO and 8% human serum albumin (HSA), or other suitable cellfreezing media. This is then diluted 1:1 with media so that the finalconcentration of DMSO and HSA are 10% and 4%, respectively. The cellsare then frozen to −80° C. at a rate of 1° per minute and stored in thevapor phase of a liquid nitrogen storage tank.

In some embodiments, the provided methods include cultivation,incubation, culture, and/or genetic engineering steps. For example, insome embodiments, provided are methods for incubating and/or engineeringthe depleted cell populations and culture-initiating compositions.

Thus, in some embodiments, the cell populations are incubated in aculture-initiating composition. The incubation and/or engineering may becarried out in a culture vessel, such as a unit, chamber, well, column,tube, tubing set, valve, vial, culture dish, bag, or other container forculture or cultivating cells.

In some embodiments, the cells are incubated and/or cultured prior to orin connection with genetic engineering. The incubation steps can includeculture, cultivation, stimulation, activation, and/or propagation. Insome embodiments, the compositions or cells are incubated in thepresence of stimulating conditions or a stimulatory agent. Suchconditions include those designed to induce proliferation, expansion,activation, and/or survival of cells in the population, to mimic antigenexposure, and/or to prime the cells for genetic engineering, such as forthe introduction of a recombinant antigen receptor.

The conditions can include one or more of particular media, temperature,oxygen content, carbon dioxide content, time, agents, e.g., nutrients,amino acids, antibiotics, ions, and/or stimulatory factors, such ascytokines, chemokines, antigens, binding partners, fusion proteins,recombinant soluble receptors, and any other agents designed to activatethe cells.

In some embodiments, the stimulating conditions or agents include one ormore agent, e.g., ligand, which is capable of activating anintracellular signaling domain of a TCR complex. In some aspects, theagent turns on or initiates TCR/CD3 intracellular signaling cascade in aT cell. Such agents can include antibodies, such as those specific for aTCR, e.g. anti-CD3. In some embodiments, the stimulating conditionsinclude one or more agent, e.g. ligand, which is capable of stimulatinga costimulatory receptor, e.g., anti-CD28. In some embodiments, suchagents and/or ligands may be, bound to solid support such as a bead,and/or one or more cytokines. Optionally, the expansion method mayfurther comprise the step of adding anti-CD3 and/or anti CD28 antibodyto the culture medium (e.g., at a concentration of at least about 0.5ng/ml). In some embodiments, the stimulating agents include IL-2, IL-15and/or IL-7. In some aspects, the IL-2 concentration is at least about10 units/mL.

In some aspects, incubation is carried out in accordance with techniquessuch as those described in U.S. Pat. No. 6,040,177 to Riddell et al.,Klebanoff et al. (2012) J Immunother. 35(9): 651-660, Terakura et al.(2012) Blood. 1:72-82, and/or Wang et al. (2012) J Immunother.35(9):689-701.

In some embodiments, the T cells are expanded by adding to theculture-initiating composition feeder cells, such as non-dividingperipheral blood mononuclear cells (PBMC), (e.g., such that theresulting population of cells contains at least about 5, 10, 20, or 40or more PBMC feeder cells for each T lymphocyte in the initialpopulation to be expanded); and incubating the culture (e.g. for a timesufficient to expand the numbers of T cells). In some aspects, thenon-dividing feeder cells can comprise gamma-irradiated PBMC feedercells. In some embodiments, the PBMC are irradiated with gamma rays inthe range of about 3000 to 3600 rads to prevent cell division. In someaspects, the feeder cells are added to culture medium prior to theaddition of the populations of T cells.

In some embodiments, the stimulating conditions include temperaturesuitable for the growth of human T lymphocytes, for example, at leastabout 25 degrees Celsius, generally at least about 30 degrees, andgenerally at or about 37 degrees Celsius. Optionally, the incubation mayfurther comprise adding non-dividing EBV-transformed lymphoblastoidcells (LCL) as feeder cells. LCL can be irradiated with gamma rays inthe range of about 6000 to 10,000 rads. The LCL feeder cells in someaspects is provided in any suitable amount, such as a ratio of LCLfeeder cells to initial T lymphocytes of at least about 10:1.

In embodiments, antigen-specific T cells, such as antigen-specific CD4+and/or CD8+ T cells, are obtained by stimulating naive or antigenspecific T lymphocytes with antigen. For example, antigen-specific Tcell lines or clones can be generated to cytomegalovirus antigens byisolating T cells from infected subjects and stimulating the cells invitro with the same antigen.

c. Engineered Cells, Vectors and Compositions for Multi-Targeting

Also provided are cells such as engineered cells that can bind to and/ortarget multiple antigens. In some embodiments, improved selectivity andspecificity is achieved through strategies targeting multiple antigens.Such strategies generally involve multiple antigen-binding domains,which typically are present on distinct genetically engineered antigenreceptors and specifically bind to distinct antigens. In someembodiments, the cells are engineered with the ability to bind more thanone antigen. For example, in some embodiments, the cells are engineeredto express multispecific binding molecules. In some embodiments, thecells express multiple binding molecules, e.g., recombinant receptors,each of which can target one antigen or multiple antigens, e.g., onereceptor that targets BCMA, such as any described herein, and anotherreceptor that targets another antigen, e.g., tumor antigen. In someaspects, a plurality of genetically engineered antigen receptors areintroduced into the cell, which specifically bind to different antigens,each expressed in or on the disease or condition to be targeted with thecells or tissues or cells thereof. Such features can in some aspectsaddress or reduce the likelihood of off-target effects or increaseefficacy. For example, where a single antigen expressed in a disease orcondition is also expressed on or in non-diseased or normal cells, suchmulti-targeting approaches can provide selectivity for desired celltypes by requiring binding via multiple antigen receptors in order toactivate the cell or induce a particular effector function. In someembodiments, a plurality of cells can be engineered to express one ormore different binding molecules, e.g., recombinant receptors, each ofwhich can target one antigen or multiple antigens.

Also provided are multispecific cells containing any of the bindingmolecules described herein, such as cells containing a cell surfaceprotein including the anti-BCMA antibody and an additional cell surfaceprotein, such as an additional chimeric receptor, which binds to adifferent antigen or a different epitope on BCMA. In some embodiments,provided are compositions of cells that express recombinant receptors,wherein one or more of the binding molecules, multispecific bindingmolecules and/or recombinant receptors bind and/or target BCMA. Alsoprovided are compositions of cells containing a plurality of cells thatexpress one or more different binding molecules, e.g., recombinantreceptors that can target one or multiple antigens. In some embodiments,the multispecific binding molecules and/or recombinant receptors targetone or more different epitopes on BCMA.

In some embodiments, provided are composition of cells, wherein eachtype of cell expresses one or more binding molecules, e.g., recombinantreceptors. In some embodiments, the cell comprises (e.g., has beentransformed with) one or more vectors comprising one or more nucleicacid that encodes one or more an amino acid sequence comprising one ormore antibodies and/or portions thereof, e.g., antigen-binding fragmentsthereof. In some embodiments, one or more such cells are provided. Insome embodiments, a composition containing one or more such cells isprovided. In some embodiments, the one or more cells can expressdifferent antibodies, or the same antibody. In some embodiments, each ofthe cells expresses one or more antibodies, such as more than oneantibody. In some embodiments, each of the cells expresses amultispecific binding molecule, e.g., a multispecific receptor, e.g.,CAR.

In some embodiments, the cells include multi-targeting strategies thattarget BCMA and a second or additional antigen associated with aparticular disease or condition. In some embodiments, the second oradditional antigen is targeted by a multispecific binding moleculeand/or multiple binding molecules and/or a plurality of cells, e.g., oneor more cells, each engineered to express one or more recombinantreceptors. In some embodiments, a recombinant receptor targeting asecond or additional antigen is expressed on the same cell as a BCMAbinding molecule, or on a different cell.

In some embodiments, among the second or additional antigens formulti-targeting strategies includes those in which at least one of theantigens is a universal tumor antigen, or a family member thereof. Insome embodiments, the second or additional antigen is an antigenexpressed on a tumor. In some embodiments, the BCMA-binding moleculesprovided herein target an antigen on the same tumor type as the secondor additional antigen. In some embodiments, the second or additionalantigen may also be a universal tumor antigen or may be a tumor antigenspecific to a tumor type. In some embodiments, the cell furthercomprises an additional genetically engineered antigen receptor thatrecognizes a second or additional antigen expressed on a disease orcondition to be treated and induces a stimulatory or activating signal.

Exemplary antigens include CD4, CD5, CD8, CD14, CD15, CD19, CD20, CD21,CD22, CD23, CD25, CD33, CD37, CD38, CD40, CD40L, CD46, CD52, CD54, CD74,CD80, CD126, CD138, B7, MUC-1, Ia, HM1.24, HLA-DR, tenascin, anangiogenesis factor, VEGF, PIGF, ED-B fibronectin, an oncogene, anoncogene product, CD66a-d, necrosis antigens, Ii, IL-2, T101, TAC, IL-6,ROR1, TRAIL-R1 (DR4), TRAIL-R2 (DR5), B cell maturation antigen (BCMA),tEGFR, Her2, L1-CAM, mesothelin, CEA, hepatitis B surface antigen,anti-folate receptor, CD24, CD30, CD44, EGFR, EGP-2, EGP-4, EPHa2,ErbB2, ErbB3, ErbB4, erbB dimers, EGFR vIII, FBP, FCRLS, FCRHS, fetalacetylcholine receptor, GD2, GD3, HMW-MAA, IL-22R-alpha, IL-13R-alpha2,kdr, kappa light chain, Lewis Y, L1-cell adhesion molecule (L1-CAM),Melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, Preferentiallyexpressed antigen of melanoma (PRAME), survivin, EGP2, EGP40, TAG72,B7-H6, IL-13 receptor a2 (IL-13Ra2), CA9, CD171, G250/CAIX, HLA-AI MAGEA1, HLA-A2 NY-ESO-1, PSCA, folate receptor-a, CD44v6, CD44v7/8, avb6integrin, 8H9, NCAM, VEGF receptors, 5T4, Foetal AchR, NKG2D ligands,dual antigen, an antigen associated with a universal tag, acancer-testes antigen, MUC1, MUC16, NY-ESO-1, MART-1, gp100, oncofetalantigen, VEGF-R2, carcinoembryonic antigen (CEA), prostate specificantigen, PSMA, Her2/neu, estrogen receptor, progesterone receptor,ephrinB2, CD123, c-Met, GD-2, 0-acetylated GD2 (OGD2), CE7, Wilms Tumor1 (WT-1), a cyclin, cyclin A2, CCL-1, hTERT, MDM2, CYP1B, WT1, livin,AFP, p53, cyclin (D1), CS-1, BCMA, BAFF-R, TACI, CD56, TIM-3, CD123,L1-cell adhesion molecule, MAGE-A1, MAGE A3, a cyclin, such as cyclin A1(CCNA1) and/or a pathogen-specific antigen, biotinylated molecules,molecules expressed by HIV, HCV, HBV and/or other pathogens, and/or insome aspects, neoepitopes or neoantigens thereof. In some embodiments,the antigen is associated with or is a universal tag.

In some embodiments, the plurality of antigens, e.g., the first antigen,e.g., BCMA, and the second or additional antigens, are expressed on thecell, tissue, or disease or condition being targeted, such as on thecancer cell. In some aspects, the cell, tissue, disease or condition ismultiple myeloma or a multiple myeloma cell. One or more of theplurality of antigens generally also is expressed on a cell which it isnot desired to target with the cell therapy, such as a normal ornon-diseased cell or tissue, and/or the engineered cells themselves. Insuch embodiments, by requiring ligation of multiple receptors to achievea response of the cell, specificity and/or efficacy is/are achieved.

In some aspects, the antigen, e.g., the second or additional antigen,such as the disease-specific antigen and/or related antigen, isexpressed on multiple myeloma, such as CD38 (cyclic ADP ribosehydrolase), CD138 (syndecan-1, syndecan, SYN-1), CS-1 (CS1, CD2 subset1, CRACC, SLAMF7, CD319, and 19A24), BAFF-R, TACI and/or FcRH5. Otherexemplary multiple myeloma antigens include CD56, TIM-3, CD33, CD123,CD44, CD20, CD40, CD74, CD200, EGFR, β2-Microglobulin, HM1.24, IGF-1R,IL-6R, TRAIL-R1, and the activin receptor type IIA (ActRIIA). See Bensonand Byrd, J. Clin. Oncol. (2012) 30(16): 2013-15; Tao and Anderson, BoneMarrow Research (2011):924058; Chu et al., Leukemia (2013) 28(4):917-27;Garfall et al., Discov Med. (2014) 17(91):37-46. In some embodiments,the antigens include those present on lymphoid tumors, myeloma,AIDS-associated lymphoma, and/or post-transplant lymphoproliferations,such as CD38. Antibodies or antigen-binding fragments directed againstsuch antigens are known and include, for example, those described inU.S. Pat. Nos. 8,153,765; 8,603,477, 8,008,450; U.S. Pub. No.US20120189622 or US20100260748; and/or International PCT PublicationNos. WO2006099875, WO2009080829 or WO2012092612 or WO2014210064. In someembodiments, such antibodies or antigen-binding fragments thereof (e.g.scFv) are contained in multispecific antibodies, multispecific chimericreceptors, such as multispecific CARs, and/or multispecific cells.

In some embodiments, the cells and methods include multi-targetingstrategies, such as expression of two or more genetically engineeredreceptors on the cell, each recognizing a different antigen andtypically each including a different intracellular signaling component.Such multi-targeting strategies are described, for example, inInternational Patent Application, Publication No.: WO 2014055668 A1(describing combinations of activating and costimulatory CARs, e.g.,targeting two different antigens present individually on off-target,e.g., normal cells, but present together only on cells of the disease orcondition to be treated) and Fedorov et al., Sci. Transl. Medicine,5(215) (December, 2013) (describing cells expressing an activating andan inhibitory CAR, such as those in which the activating CAR binds toone antigen expressed on both normal or non-diseased cells and cells ofthe disease or condition to be treated, and the inhibitory CAR binds toanother antigen expressed only on the normal cells or cells which it isnot desired to treat).

In some embodiments, a plurality of cells, each engineered to expressone or more recombinant receptors, are provided. For example, in someembodiments, one cell is engineered to express a binding molecule thatbinds and/or targets BCMA, and another cell is engineered to express abinding molecule that binds and/or targets an additional or secondantigen. In some embodiments, the cells can each express a multispecificbinding molecule, e.g., a multispecific recombinant receptor, where oneor more of the target antigen is BCMA. In some of such embodiments, theplurality of cells can be administered together or separately. In someembodiments, some of the plurality of cells are administeredsimultaneously or concurrently with other cells, e.g., administered onthe same day, and/or sequentially with or intermittently with, in anyorder, another engineered cell in the plurality. For example, in someembodiments, an engineered cell expressing a BCMA-binding molecule,e.g., CAR, is administered simultaneously with or sequentially with, inany order, another engineered cell expressing a binding molecule thatbinds a different target antigen or a different epitope on BCMA. In someembodiments, the plurality of cells can be in the same composition or indifferent compositions. Exemplary compositions of the cells includecompositions described in Section II below.

II. PHARMACEUTICAL COMPOSITIONS

Also provided are compositions including the BCMA-binding molecules,immunoconjugates, recombinant receptors, and engineered cells, includingpharmaceutical compositions and formulations.

Provided are pharmaceutical formulations comprising a BCMA-bindingmolecule (e.g., antibody), an immunoconjugate, a recombinant receptor(e.g., chimeric antigen receptor), engineered cells expressing saidmolecules (e.g., recombinant receptor), a plurality of engineered cellsexpressing said molecules (e.g., recombinant receptor) and/or additionalagents for combination treatment or therapy. The pharmaceuticalcompositions and formulations generally include one or more optionalpharmaceutically acceptable carrier or excipient. In some embodiments,the composition includes at least one additional therapeutic agent.

The term “pharmaceutical formulation” refers to a preparation which isin such form as to permit the biological activity of an activeingredient contained therein to be effective, and which contains noadditional components which are unacceptably toxic to a subject to whichthe formulation would be administered.

A “pharmaceutically acceptable carrier” refers to an ingredient in apharmaceutical formulation, other than an active ingredient, which isnontoxic to a subject. A pharmaceutically acceptable carrier includes,but is not limited to, a buffer, excipient, stabilizer, or preservative.

In some aspects, the choice of carrier is determined in part by theparticular cell, binding molecule, and/or antibody, and/or by the methodof administration. Accordingly, there are a variety of suitableformulations. For example, the pharmaceutical composition can containpreservatives. Suitable preservatives may include, for example,methylparaben, propylparaben, sodium benzoate, and benzalkoniumchloride. In some aspects, a mixture of two or more preservatives isused. The preservative or mixtures thereof are typically present in anamount of about 0.0001% to about 2% by weight of the total composition.Carriers are described, e.g., by Remington's Pharmaceutical Sciences16th edition, Osol, A. Ed. (1980). Pharmaceutically acceptable carriersare generally nontoxic to recipients at the dosages and concentrationsemployed, and include, but are not limited to: buffers such asphosphate, citrate, and other organic acids; antioxidants includingascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride; benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides, and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g. Zn-protein complexes); and/or non-ionicsurfactants such as polyethylene glycol (PEG).

Buffering agents in some aspects are included in the compositions.Suitable buffering agents include, for example, citric acid, sodiumcitrate, phosphoric acid, potassium phosphate, and various other acidsand salts. In some aspects, a mixture of two or more buffering agents isused. The buffering agent or mixtures thereof are typically present inan amount of about 0.001% to about 4% by weight of the totalcomposition. Methods for preparing administrable pharmaceuticalcompositions are known. Exemplary methods are described in more detailin, for example, Remington: The Science and Practice of Pharmacy,Lippincott Williams & Wilkins; 21st ed. (May 1, 2005).

Formulations of the antibodies described herein can include lyophilizedformulations and aqueous solutions.

The formulation or composition may also contain more than one activeingredient useful for the particular indication, disease, or conditionbeing treated with the binding molecules or cells, preferably those withactivities complementary to the binding molecule or cell, where therespective activities do not adversely affect one another. Such activeingredients are suitably present in combination in amounts that areeffective for the purpose intended. Thus, in some embodiments, thepharmaceutical composition further includes other pharmaceuticallyactive agents or drugs, such as chemotherapeutic agents, e.g.,asparaginase, busulfan, carboplatin, cisplatin, daunorubicin,doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate,paclitaxel, rituximab, vinblastine, vincristine, etc. In someembodiments, the cells or antibodies are administered in the form of asalt, e.g., a pharmaceutically acceptable salt. Suitablepharmaceutically acceptable acid addition salts include those derivedfrom mineral acids, such as hydrochloric, hydrobromic, phosphoric,metaphosphoric, nitric, and sulphuric acids, and organic acids, such astartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic,gluconic, succinic, and arylsulphonic acids, for example,p-toluenesulphonic acid.

Active ingredients may be entrapped in microcapsules, in colloidal drugdelivery systems (for example, liposomes, albumin microspheres,microemulsions, nano-particles and nanocapsules) or in macroemulsions.In certain embodiments, the pharmaceutical composition is formulated asan inclusion complex, such as cyclodextrin inclusion complex, or as aliposome. Liposomes can serve to target the host cells (e.g., T-cells orNK cells) to a particular tissue. Many methods are available forpreparing liposomes, such as those described in, for example, Szoka etal., Ann. Rev. Biophys. Bioeng., 9: 467 (1980), and U.S. Pat. Nos.4,235,871, 4,501,728, 4,837,028, and 5,019,369.

The pharmaceutical composition in some aspects can employ time-released,delayed release, and sustained release delivery systems such that thedelivery of the composition occurs prior to, and with sufficient time tocause, sensitization of the site to be treated. Many types of releasedelivery systems are available and known. Such systems can avoidrepeated administrations of the composition, thereby increasingconvenience to the subject and the physician.

The pharmaceutical composition in some embodiments contains the bindingmolecules and/or cells in amounts effective to treat or prevent thedisease or condition, such as a therapeutically effective orprophylactically effective amount. Therapeutic or prophylactic efficacyin some embodiments is monitored by periodic assessment of treatedsubjects. For repeated administrations over several days or longer,depending on the condition, the treatment is repeated until a desiredsuppression of disease symptoms occurs. However, other dosage regimensmay be useful and can be determined. The desired dosage can be deliveredby a single bolus administration of the composition, by multiple bolusadministrations of the composition, or by continuous infusionadministration of the composition.

In certain embodiments, in the context of genetically engineered cellscontaining the binding molecules, a subject is administered the range ofabout one million to about 100 billion cells, such as, e.g., 1 millionto about 50 billion cells (e.g., about 5 million cells, about 25 millioncells, about 500 million cells, about 1 billion cells, about 5 billioncells, about 20 billion cells, about 30 billion cells, about 40 billioncells, or a range defined by any two of the foregoing values), such asabout 10 million to about 100 billion cells (e.g., about 20 millioncells, about 30 million cells, about 40 million cells, about 60 millioncells, about 70 million cells, about 80 million cells, about 90 millioncells, about 10 billion cells, about 25 billion cells, about 50 billioncells, about 75 billion cells, about 90 billion cells, or a rangedefined by any two of the foregoing values), and in some cases about 100million cells to about 50 billion cells (e.g., about 120 million cells,about 250 million cells, about 350 million cells, about 450 millioncells, about 650 million cells, about 800 million cells, about 900million cells, about 3 billion cells, about 30 billion cells, about 45billion cells) or any value in between these ranges, and/or such anumber of cells per kilogram of body weight of the subject.

The may be administered using standard administration techniques,formulations, and/or devices. Provided are formulations and devices,such as syringes and vials, for storage and administration of thecompositions. Administration of the cells can be autologous orheterologous. For example, immunoresponsive cells or progenitors can beobtained from one subject, and administered to the same subject or adifferent, compatible subject. Peripheral blood derived immunoresponsivecells or their progeny (e.g., in vivo, ex vivo or in vitro derived) canbe administered via localized injection, including catheteradministration, systemic injection, localized injection, intravenousinjection, or parenteral administration. When administering atherapeutic composition (e.g., a pharmaceutical composition containing agenetically modified immunoresponsive cell), it will generally beformulated in a unit dosage injectable form (solution, suspension,emulsion).

Formulations include those for oral, intravenous, intraperitoneal,subcutaneous, pulmonary, transdermal, intramuscular, intranasal, buccal,sublingual, or suppository administration. In some embodiments, the cellpopulations are administered parenterally. The term “parenteral,” asused herein, includes intravenous, intramuscular, subcutaneous, rectal,vaginal, intracranial, intrathoracic, and intraperitonealadministration. In some embodiments, the cell populations areadministered to a subject using peripheral systemic delivery byintravenous, intraperitoneal, or subcutaneous injection.

Compositions in some embodiments are provided as sterile liquidpreparations, e.g., isotonic aqueous solutions, suspensions, emulsions,dispersions, or viscous compositions, which may in some aspects bebuffered to a selected pH. Liquid preparations are normally easier toprepare than gels, other viscous compositions, and solid compositions.Additionally, liquid compositions are somewhat more convenient toadminister, especially by injection. Viscous compositions, on the otherhand, can be formulated within the appropriate viscosity range toprovide longer contact periods with specific tissues. Liquid or viscouscompositions can comprise carriers, which can be a solvent or dispersingmedium containing, for example, water, saline, phosphate bufferedsaline, polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycol) and suitable mixtures thereof.

Sterile injectable solutions can be prepared by incorporating thebinding molecule in a solvent, such as in admixture with a suitablecarrier, diluent, or excipient such as sterile water, physiologicalsaline, glucose, dextrose, or the like. The compositions can also belyophilized. The compositions can contain auxiliary substances such aswetting, dispersing, or emulsifying agents (e.g., methylcellulose), pHbuffering agents, gelling or viscosity enhancing additives,preservatives, flavoring agents, colors, and the like, depending uponthe route of administration and the preparation desired. Standard textsmay in some aspects be consulted to prepare suitable preparations.

Various additives which enhance the stability and sterility of thecompositions, including antimicrobial preservatives, antioxidants,chelating agents, and buffers, can be added. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the use of agents delaying absorption, for example,aluminum monostearate and gelatin.

Sustained-release preparations may be prepared. Suitable examples ofsustained-release preparations include semipermeable matrices of solidhydrophobic polymers containing the antibody, which matrices are in theform of shaped articles, e.g. films, or microcapsules.

The formulations to be used for in vivo administration are generallysterile. Sterility may be readily accomplished, e.g., by filtrationthrough sterile filtration membranes.

Also provided are pharmaceutical compositions for combination therapy.Any of the additional agents for combination therapy described herein,such as agents described in Section III.B, can be prepared andadministered as one or more pharmaceutical compositions, with theBCMA-binding molecule (e.g., antibody), immunoconjugate, recombinantreceptor (e.g., chimeric antigen receptor) and/or engineered cellsexpressing said molecules (e.g., recombinant receptor) described herein.The combination therapy can be administered in one or morepharmaceutical compositions, e.g., where the binding molecules,recombinant receptors and/or cells are in the same pharmaceuticalcomposition as the additional agent, or in separate pharmaceuticalcompositions. For example, in some embodiments, the additional agent isan additional engineered cell, e.g., cell engineered to express adifferent recombinant receptor that targets a different antigen or adifferent epitope on BCMA, and is administered in the same compositionor in a separate composition. In some embodiments, each of thepharmaceutical composition is formulated in a suitable formulationaccording to the particular binding molecule, recombinant receptor,cell, e.g., engineered cell, and/or additional agent, and the particulardosage regimen and/or method of delivery.

III. METHODS AND USES

Also provided methods, such as methods of treatment, of using and usesof the BCMA-binding molecules, immunoconjugates, recombinant receptors,engineered cells, and pharmaceutical compositions and formulationsthereof, such as in the treatment of diseases, conditions, and disordersin which BCMA is expressed, and/or detection, diagnostic, and prognosticmethods. Also provided are methods of combination therapy and/ortreatment.

A. Therapeutic and Prophylactic Methods and Uses

Also provided are methods of administering and uses, such as therapeuticand prophylactic uses, of the BCMA-binding molecules, including theanti-BCMA antibodies, e.g., antibody fragments and proteins containingthe same such as the recombinant receptors (e.g., CARs), engineeredcells expressing the recombinant receptors (e.g., CARs), plurality ofengineered cells expressing the receptors, and/or compositionscomprising the same. Such methods and uses include therapeutic methodsand uses, for example, involving administration of the molecules (e.g.,BCMA-binding molecules, recombinant receptors), cells (e.g., engineeredcells), or compositions containing the same, to a subject having adisease, condition, or disorder associated with BCMA such as a disease,condition, or disorder associated with BCMA expression, and/or in whichcells or tissues express, e.g., specifically express BCMA. In someembodiments, the molecule, cell, and/or composition is administered inan effective amount to effect treatment of the disease or disorder.Provided herein are uses of the binding molecules (e.g., anti-BCMAantibodies or antigen-binding fragments thereof), recombinant receptors(e.g., CARs), and cells (e.g., engineered cells) in such methods andtreatments, and in the preparation of a medicament in order to carry outsuch therapeutic methods. In some embodiments, the methods are carriedout by administering the binding molecules or cells, or compositionscomprising the same, to the subject having, having had, or suspected ofhaving the disease or condition. In some embodiments, the methodsthereby treat the disease or condition or disorder in the subject. Alsoprovided herein are of use of any of the compositions, such aspharmaceutical compositions provided herein, for the treatment of adisease or disorder associated with BCMA, for example, multiple myeloma.

As used herein, “treatment” (and grammatical variations thereof such as“treat” or “treating”) refers to complete or partial amelioration orreduction of a disease or condition or disorder, or a symptom, adverseeffect or outcome, or phenotype associated therewith. Desirable effectsof treatment include, but are not limited to, preventing occurrence orrecurrence of disease, alleviation of symptoms, diminishment of anydirect or indirect pathological consequences of the disease, preventingmetastasis, decreasing the rate of disease progression, amelioration orpalliation of the disease state, and remission or improved prognosis.The terms do not imply complete curing of a disease or completeelimination of any symptom or effect(s) on all symptoms or outcomes.

As used herein, “delaying development of a disease” means to defer,hinder, slow, retard, stabilize, suppress and/or postpone development ofthe disease (such as cancer). This delay can be of varying lengths oftime, depending on the history of the disease and/or subject beingtreated. As is evident to one skilled in the art, a sufficient orsignificant delay can, in effect, encompass prevention, in that thesubject does not develop the disease. For example, a late stage cancer,such as development of metastasis, may be delayed.

“Preventing,” as used herein, includes providing prophylaxis withrespect to the occurrence or recurrence of a disease in a subject thatmay be predisposed to the disease but has not yet been diagnosed withthe disease. In some embodiments, the provided molecules andcompositions are used to delay development of a disease or to slow theprogression of a disease.

As used herein, to “suppress” a function or activity is to reduce thefunction or activity when compared to otherwise same conditions exceptfor a condition or parameter of interest, or alternatively, as comparedto another condition. For example, an antibody or composition or cellwhich suppresses tumor growth reduces the rate of growth of the tumorcompared to the rate of growth of the tumor in the absence of theantibody or composition or cell.

An “effective amount” of an agent, e.g., a pharmaceutical formulation,binding molecule, antibody, cells, or composition, in the context ofadministration, refers to an amount effective, at dosages/amounts andfor periods of time necessary, to achieve a desired result, such as atherapeutic or prophylactic result.

A “therapeutically effective amount” of an agent, e.g., a pharmaceuticalformulation, binding molecule, antibody, cells, or composition refers toan amount effective, at dosages and for periods of time necessary, toachieve a desired therapeutic result, such as for treatment of adisease, condition, or disorder, and/or pharmacokinetic orpharmacodynamic effect of the treatment. The therapeutically effectiveamount may vary according to factors such as the disease state, age,sex, and weight of the subject, and the populations of cellsadministered. In some embodiments, the provided methods involveadministering the molecules, antibodies, cells, and/or compositions ateffective amounts, e.g., therapeutically effective amounts.

A “prophylactically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredprophylactic result. Typically but not necessarily, since a prophylacticdose is used in subjects prior to or at an earlier stage of disease, theprophylactically effective amount will be less than the therapeuticallyeffective amount.

As used herein, a “subject” or an “individual” is a mammal. In someembodiments, a “mammal” includes humans, non-human primates, domesticand farm animals, and zoo, sports, or pet animals, such as dogs, horses,rabbits, cattle, pigs, hamsters, gerbils, mice, ferrets, rats, cats,monkeys, etc. In some embodiments, the subject is human.

Among the diseases to be treated is any disease or disorder associatedwith BCMA or any disease or disorder in which BCMA is specificallyexpressed and/or in which BCMA has been targeted for treatment (alsoreferred to herein interchangeably as a “BCMA-associated disease ordisorder”). Cancers associated with BCMA expression include hematologicmalignancies such as multiple myeloma, Waldenstrom macroglobulinemia aswell as both Hodgkin's and non-Hodgkin's lymphomas. See Coquery et al.,Crit Rev Immunol., 2012, 32(4):287-305 for a review of BCMA. Since BCMAhas been implicated in mediating tumor cell survival, it is a potentialtarget for cancer therapy. Anti-BCMA antibodies have been previouslydescribed such as the inhibitory anti-BCMA antibody SG1 which promotedantibody-dependent cell-mediated cytotoxicity of BCMA-expressingmultiple myeloma cells. See Ryan et al., Mol Cancer Ther., 2007,6(11):3009-3018 and International PCT Pub. No. WO2010/104949. Chimericantigen receptors containing mouse anti-human BCMA antibodies and cellsexpressing such chimeric receptors have also been previously described.See Carpenter et al., Clin Cancer Res., 2013, 19(8):2048-2060.

In some embodiments, the disease or disorder associated with BCMA is a Bcell-related disorder. In some embodiments, the disease or disorderassociated with BCMA is one or more diseases or conditions from amongglioblastoma, lymphomatoid granulomatosis, post-transplantlymphoproliferative disorder, an immunoregulatory disorder, heavy-chaindisease, primary or immunocyte-associated amyloidosis, or monoclonalgammopathy of undetermined significance.

In some embodiments, the disease or disorder associated with BCMA is anautoimmune disease or disorder. Such autoimmune diseases or disorderinclude, but are not limited to, systemic lupus erythematosus (SLE),lupus nephritis, inflammatory bowel disease, rheumatoid arthritis (e.g.,juvenile rheumatoid arthritis), ANCA associated vasculitis, idiopathicthrombocytopenia purpura (ITP), thrombotic thrombocytopenia purpura(TTP), autoimmune thrombocytopenia, Chagas' disease, Grave's disease,Wegener's granulomatosis, poly-arteritis nodosa, Sjogren's syndrome,pemphigus vulgaris, scleroderma, multiple sclerosis, psoriasis, IgAnephropathy, IgM polyneuropathies, vasculitis, diabetes mellitus,Reynaud's syndrome, anti-phospholipid syndrome, Goodpasture's disease,Kawasaki disease, autoimmune hemolytic anemia, myasthenia gravis, orprogressive glomerulonephritis.

In certain diseases and conditions, BCMA is expressed on malignant cellsand cancers. In some embodiments, the cancer (e.g., a BCMA-expressingcancer) is a B cell malignancy. In some embodiments, the cancer (e.g., aBCMA-expressing cancer) is a leukemia (e.g., B cell leukemia), lymphoma(e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, etc.), or a myeloma,e.g., a multiple myeloma (MM), a plasma cell malignancy (e.g.,plasmacytoma). Lymphomas contemplated herein include, but are notlimited to, Burkitt lymphoma (e.g., endemic Burkitt's lymphoma orsporadic Burkitt's lymphoma), non-Hodgkin's lymphoma (NHL), Hodgkin'slymphoma, Waldenstrom macroglobulinemia, follicular lymphoma, smallnon-cleaved cell lymphoma, mucosa-associated lymphatic tissue lymphoma(MALT), marginal zone lymphoma, splenic lymphoma, nodal monocytoid Bcell lymphoma, immunoblastic lymphoma, large cell lymphoma, diffusemixed cell lymphoma, pulmonary B cell angiocentric lymphoma, smalllymphocytic lymphoma, primary mediastinal B cell lymphoma,lymphoplasmacytic lymphoma (LPL), or mantle cell lymphoma (MCL).Leukemias contemplated here, include, but are not limited to, chroniclymphocytic leukemia (CLL), plasma cell leukemia or acute lymphocyticleukemia (ALL). Also contemplated herein are myelomas, e.g., multiplemyeloma (MM, e.g., non-secretory multiple myeloma, smoldering multiplemyeloma). Also contemplated herein are plasma cell malignanciesincluding, but not limited to, plasmacytoma. Among the diseases,disorders or conditions associated with BCMA (e.g., a BCMA-expressingcancer) that can be treated include, but are not limited to,neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer,breast cancer, epithelial squamous cell cancer, melanoma, myeloma (e.g.,multiple myeloma), stomach cancer, brain cancer, lung cancer, pancreaticcancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer,prostate cancer, testicular cancer, thyroid cancer, uterine cancer,adrenal cancer and head and neck cancer.

In some embodiments, the methods may identify a subject who has, issuspected to have, or is at risk for developing a BCMA-associateddisease or disorder. Hence, provided are methods for identifyingsubjects with diseases or disorders associated with elevated BCMAexpression and selecting them for treatment with a provided BCMA-bindingmolecule, including any of the anti-BCMA antibodies, e.g., antibodyfragments and proteins containing the same such as the recombinantreceptors (e.g., CARs), and/or engineered cells expressing therecombinant receptors.

For example, a subject may be screened for the presence of a disease ordisorder associated with elevated BCMA expression, such as aBCMA-expressing cancer. In some embodiments, the methods includescreening for or detecting the presence of a BCMA-associated disease,e.g. a tumor. Thus, in some aspects, a sample may be obtained from apatient suspected of having a disease or disorder associated withelevated BCMA expression and assayed for the expression level of BCMA.In some aspects, a subject who tests positive for a BCMA-associateddisease or disorder may be selected for treatment by the presentmethods, and may be administered a therapeutically effective amount of aBCMA-binding molecule (e.g., anti-BCMA antibody or antigen-bindingfragment thereof), recombinant receptor (e.g., CAR) comprising aBCMA-binding molecule, cells containing a recombinant receptor or apharmaceutical composition thereof as described herein. In someembodiments, the methods can be used to monitor the size or density of aBCMA-expressing tissue, e.g. tumor, over time, e.g., before, during, orafter treatment by the methods.

In some embodiments, the subject has persistent or relapsed disease,e.g., following treatment with another BCMA-specific antibody and/orcells expressing a BCMA-targeting chimeric receptor and/or othertherapy, including chemotherapy, radiation, and/or hematopoietic stemcell transplantation (HSCT), e.g., allogenic HSCT. In some embodiments,the administration effectively treats the subject despite the subjecthaving become resistant to another BCMA-targeted therapy. In someembodiments, the subject has not relapsed but is determined to be atrisk for relapse, such as at a high risk of relapse, and thus thecompound or composition is administered prophylactically, e.g., toreduce the likelihood of or prevent relapse.

In some embodiments, the treatment does not induce an immune response bythe subject to the therapy, and/or does not induce such a response to adegree that prevents effective treatment of the disease or condition. Insome aspects, the degree of immunogenicity and/or graft versus hostresponse is less than that observed with a different but comparabletreatment. For example, in the case of adoptive cell therapy using cellsexpressing CARs including the provided anti-BCMA antibodies, the degreeof immunogenicity in some embodiments is reduced compared to CARsincluding a different antibody that binds to a similar, e.g.,overlapping epitope and/or that competes for binding to BCMA with theprovided antibody, such as a mouse or monkey or rabbit or humanizedantibody.

In some embodiments, the methods include adoptive cell therapy, wherebygenetically engineered cells expressing the provided recombinantreceptors comprising a BCMA-binding molecule (e.g., CARs comprisinganti-BCMA antibody or antigen-binding fragment thereof) are administeredto subjects. Such administration can promote activation of the cells(e.g., T cell activation) in a BCMA-targeted manner, such that the cellsof the disease or disorder are targeted for destruction.

Thus, the provided methods and uses include methods and uses foradoptive cell therapy. In some embodiments, the methods includeadministration of the cells, the plurality of cells a compositioncontaining the cells or the plurality of cells to a subject, tissue, orcell, such as one having, at risk for, or suspected of having thedisease, condition or disorder. In some embodiments, the cells,populations, and compositions are administered to a subject having theparticular disease or condition to be treated, e.g., via adoptive celltherapy, such as adoptive T cell therapy. In some embodiments, the cellsor compositions are administered to the subject, such as a subjecthaving or at risk for the disease or condition. In some aspects, themethods thereby treat, e.g., ameliorate one or more symptom of thedisease or condition, such as by lessening tumor burden in aBCMA-expressing cancer.

Methods for administration of cells for adoptive cell therapy are knownand may be used in connection with the provided methods andcompositions. For example, adoptive T cell therapy methods aredescribed, e.g., in US Patent Application Publication No. 2003/0170238to Gruenberg et al; U.S. Pat. No. 4,690,915 to Rosenberg; Rosenberg(2011) Nat Rev Clin Oncol. 8(10):577-85). See, e.g., Themeli et al.(2013) Nat Biotechnol. 31(10): 928-933; Tsukahara et al. (2013) BiochemBiophys Res Commun 438(1): 84-9; Davila et al. (2013) PLoS ONE 8(4):e61338.

In some embodiments, the cell therapy, e.g., adoptive cell therapy,e.g., adoptive T cell therapy, is carried out by autologous transfer, inwhich the cells are isolated and/or otherwise prepared from the subjectwho is to receive the cell therapy, or from a sample derived from such asubject. Thus, in some aspects, the cells are derived from a subject,e.g., patient, in need of a treatment and the cells, following isolationand processing are administered to the same subject.

In some embodiments, the cell therapy, e.g., adoptive cell therapy,e.g., adoptive T cell therapy, is carried out by allogeneic transfer, inwhich the cells are isolated and/or otherwise prepared from a subjectother than a subject who is to receive or who ultimately receives thecell therapy, e.g., a first subject. In such embodiments, the cells thenare administered to a different subject, e.g., a second subject, of thesame species. In some embodiments, the first and second subjects aregenetically identical. In some embodiments, the first and secondsubjects are genetically similar. In some embodiments, the secondsubject expresses the same HLA class or supertype as the first subject.

In some embodiments, the subject, to whom the cells, cell populations,or compositions are administered is a primate, such as a human. In someembodiments, the subject, to whom the cells, cell populations, orcompositions are administered is a non-human primate. In someembodiments, the non-human primate is a monkey (e.g., cynomolgus monkey)or an ape. The subject can be male or female and can be any suitableage, including infant, juvenile, adolescent, adult, and geriatricsubjects. In some embodiments, the subject is a non-primate mammal, suchas a rodent (e.g., mouse, rat, etc.). In some examples, the patient orsubject is a validated animal model for disease, adoptive cell therapy,and/or for assessing toxic outcomes such as cytokine release syndrome(CRS).

The BCMA-binding molecules such as antibodies, recombinant receptors(e.g., CARs) containing the antibodies and cells expressing the same,can be administered by any suitable means, for example, by injection,e.g., intravenous or subcutaneous injections, intraocular injection,periocular injection, subretinal injection, intravitreal injection,trans-septal injection, subscleral injection, intrachoroidal injection,intracameral injection, subconjunctival injection, subconjunctivalinjection, sub-Tenon's injection, retrobulbar injection, peribulbarinjection, or posterior juxtascleral delivery. In some embodiments, theyare administered by parenteral, intrapulmonary, and intranasal, and, ifdesired for local treatment, intralesional administration. Parenteralinfusions include intramuscular, intravenous, intraarterial,intraperitoneal, intracranial, intrathoracic, or subcutaneousadministration. Dosing and administration may depend in part on whetherthe administration is brief or chronic. Various dosing schedules includebut are not limited to single or multiple administrations over varioustime-points, bolus administration, and pulse infusion.

For the prevention or treatment of disease, the appropriate dosage ofthe binding molecule, recombinant receptor or cell may depend on thetype of disease to be treated, the type of binding molecule orrecombinant receptor, the severity and course of the disease, whetherthe binding molecule or recombinant receptor is administered forpreventive or therapeutic purposes, previous therapy, the patient'sclinical history and response to the binding molecule, recombinantreceptor or cell, and the discretion of the attending physician. Thecompositions and molecules and cells are in some embodiments suitablyadministered to the patient at one time or over a series of treatments.

Depending on the type and severity of the disease, dosages of bindingmolecules (e.g., anti-BCMA antibody or antigen-binding fragment thereof)or recombinant receptors may include about 1 μg/kg to about 15 mg/kg(e.g. 0.1 mg/kg-10 mg/kg), about 1 μg/kg to about 100 mg/kg, about 0.05mg/kg to about 10 mg/kg, about 0.5 mg/kg, about 2.0 mg/kg, about 4.0mg/kg or about 10 mg/kg. Multiple doses may be administeredintermittently, e.g. every week or every three weeks. An initial higherloading dose, followed by one or more lower doses may be administered.

In certain embodiments, in the context of genetically engineered cellscontaining the binding molecules or recombinant receptors, a subject isadministered the range of about one million to about 100 billion cellsand/or that amount of cells per kilogram of body weight, such as, e.g.,about 1 million to about 50 billion cells (e.g., about 5 million cells,about 25 million cells, about 500 million cells, about 1 billion cells,about 5 billion cells, about 20 billion cells, about 30 billion cells,about 40 billion cells, or a range defined by any two of the foregoingvalues), such as about 10 million to about 100 billion cells (e.g.,about 20 million cells, about 30 million cells, about 40 million cells,about 60 million cells, about 70 million cells, about 80 million cells,about 90 million cells, about 10 billion cells, about 25 billion cells,about 50 billion cells, about 75 billion cells, about 90 billion cells,or a range defined by any two of the foregoing values), and in somecases about 100 million cells to about 50 billion cells (e.g., about 120million cells, about 250 million cells, about 350 million cells, about450 million cells, about 650 million cells, about 800 million cells,about 900 million cells, about 3 billion cells, about 30 billion cells,about 45 billion cells) or any value in between these ranges and/or perkilogram of body weight. Again, dosages may vary depending on attributesparticular to the disease or disorder and/or patient and/or othertreatments.

In some embodiments, for example, where the subject is a human, the doseincludes fewer than about 1×10⁸ total recombinant receptor (e.g.,CAR)-expressing cells, T cells, or peripheral blood mononuclear cells(PBMCs), e.g., in the range of about 1×10⁶ to 1×10⁸ such cells, such as2×10⁶, 5×10⁶, 1×10⁷, 5×10⁷, or 1×10⁸ or total such cells, or the rangebetween any two of the foregoing values.

In some aspects, the size of the dose is determined based on one or morecriteria such as response of the subject to prior treatment, e.g.chemotherapy, disease burden in the subject, such as tumor load, bulk,size, or degree, extent, or type of metastasis, stage, and/or likelihoodor incidence of the subject developing toxic outcomes, e.g., CRS,macrophage activation syndrome, tumor lysis syndrome, neurotoxicity,and/or a host immune response against the cells and/or recombinantreceptors being administered.

In some aspects, the size of the dose is determined by the burden of thedisease or condition in the subject. For example, in some aspects, thenumber of cells administered in the dose is determined based on thetumor burden that is present in the subject immediately prior toadministration of the initiation of the dose of cells. In someembodiments, the size of the first and/or subsequent dose is inverselycorrelated with disease burden. In some aspects, as in the context of alarge disease burden, the subject is administered a low number of cells.In other embodiments, as in the context of a lower disease burden, thesubject is administered a larger number of cells.

In some embodiments, the cells, binding molecules, or recombinantreceptors are administered as part of a combination treatment, such assimultaneously with or sequentially with, in any order, anothertherapeutic intervention, such as another antibody or engineered cell orreceptor or agent, such as a cytotoxic or therapeutic agent, such as anydescribed in Section I.C or III.B.

The cells, binding molecules and/or recombinant receptors in someembodiments are co-administered with one or more additional therapeuticagents or in connection with another therapeutic intervention, eithersimultaneously or sequentially in any order. In some contexts, the cellsare co-administered with another therapy sufficiently close in time suchthat the cell populations enhance the effect of one or more additionaltherapeutic agents, or vice versa. In some embodiments, the cells,binding molecules and/or recombinant receptors are administered prior tothe one or more additional therapeutic agents. In some embodiments, thecells, binding molecules and/or recombinant receptors are administeredafter to the one or more additional therapeutic agents.

Once the cells are administered to a mammal (e.g., a human), thebiological activity of the engineered cell populations and/or antibodiesin some aspects is measured by any of a number of known methods.Parameters to assess include specific binding of an engineered ornatural T cell or other immune cell to antigen, in vivo, e.g., byimaging, or ex vivo, e.g., by ELISA or flow cytometry. In certainembodiments, the ability of the engineered cells to destroy target cellscan be measured using any suitable method known in the art, such ascytotoxicity assays described in, for example, Kochenderfer et al., J.Immunotherapy, 32(7): 689-702 (2009), and Herman et al. J. ImmunologicalMethods, 285(1): 25-40 (2004). In certain embodiments, the biologicalactivity of the cells also can be measured by assaying expression and/orsecretion of certain cytokines, such as CD 107a, IFNγ, IL-2, and TNF. Insome aspects the biological activity is measured by assessing clinicaloutcome, such as reduction in tumor burden or load.

In certain embodiments, engineered cells are modified in any number ofways, such that their therapeutic or prophylactic efficacy is increased.For example, the engineered CAR or TCR expressed by the population insome embodiments are conjugated either directly or indirectly through alinker to a targeting moiety. The practice of conjugating compounds,e.g., the CAR or TCR, to targeting moieties is known in the art. See,for instance, Wadwa et al., J. Drug Targeting, 3(2):111 (1995), and U.S.Pat. No. 5,087,616.

B. Combination Therapy

Also provided are methods of combination therapy that includesadministering and uses, such as therapeutic and prophylactic uses, ofthe BCMA-binding molecules, including the anti-BCMA antibodies, e.g.,antibody fragments and proteins containing the same such as therecombinant receptors (e.g., CARs), engineered cells expressing therecombinant receptors (e.g., CARs), plurality of engineered cellsexpressing the receptors, and/or compositions comprising the same.

In some embodiments, the BCMA-binding molecule (e.g., antibody),immunoconjugate, recombinant receptor (e.g., chimeric antigen receptor)and/or engineered cells expressing said molecules (e.g., recombinantreceptor) described herein are administered as part of a combinationtreatment or combination therapy, such as simultaneously with,sequentially with or intermittently with, in any order, one or moreadditional therapeutic intervention. In some embodiments, the one ormore additional therapeutic intervention includes, for example, anantibody, an engineered cell, a receptor and/or an agent, such as a cellexpressing a recombinant receptor, and/or cytotoxic or therapeuticagent, e.g., a chemotherapeutic agent. In some embodiments, thecombination therapy includes administration of one or more additionalagents, therapies and/or treatments, e.g., any of the additional agents,therapy and/or treatments described herein. In some embodiments, thecombination therapy includes administration of one or more additionalagents for treatment or therapy, such as an immunomodulatory agent,immune checkpoint inhibitor, adenosine pathway or adenosine receptorantagonist or agonist and kinase inhibitors. In some embodiments, thecombination treatment or combination therapy includes an additionaltreatment, such as a surgical treatment, transplant, and/or radiationtherapy. Also provided are methods of combination treatment orcombination therapy that includes administering the binding molecules(e.g., BCMA-binding molecules), recombinant receptors, cells and/orcompositions described herein and one or more additional therapeuticinterventions.

In some embodiments, the additional agent for combination treatment orcombination therapy enhances, boosts and/or promotes the efficacy and/orsafety of the therapeutic effect of binding molecules, recombinantreceptors, cells and/or compositions. In some embodiments, theadditional agent enhances or improves the efficacy, survival orpersistence of the administered cells, e.g., cells expressing thebinding molecule or a recombinant receptor. In some embodiments, theadditional agent is selected from among a protein phosphatase inhibitor,a kinase inhibitor, a cytokine, an immunomodulator, or an agent thatdecreases the level or activity of a regulatory T (Treg) cell. In someembodiments, the additional agent enhances safety, by virtue of reducingor ameliorating adverse effects of the administered binding molecules,recombinant receptors, cells and/or compositions. In some embodiments,the additional agent can treat the same disease, condition or acomorbidity. In some embodiments, the additional agent can ameliorate,reduce or eliminate one or more toxicities, adverse effects or sideeffects that are associated with administration of the bindingmolecules, recombinant receptors, cells and/or compositions, e.g.,CAR-expressing cells.

In some embodiments, the additional therapy, treatment or agent includeschemotherapy, radiation therapy, surgery, transplantation, adoptive celltherapy, antibodies, cytotoxic agents, chemotherapeutic agents,cytokines, growth inhibitory agents, anti-hormonal agents, kinaseinhibitors, anti-angiogenic agents, cardioprotectants, immunostimulatoryagents, immunosuppressive agents, immune checkpoint inhibitors,antibiotics, angiogenesis inhibitors, metabolic modulators or othertherapeutic agents or any combination thereof. In some embodiments, theadditional agent is a protein, a peptide, a nucleic acid, a smallmolecule agent, a cell, a toxin, a lipid, a carbohydrate or combinationsthereof, or any other type of therapeutic agent, e.g. radiation. In someembodiments, the additional therapy, agent or treatment includessurgery, chemotherapy, radiation therapy, transplantation,administration of cells expressing a recombinant receptor, e.g., CAR,kinase inhibitor, immune checkpoint inhibitor, mTOR pathway inhibitor,immunosuppressive agents, immunomodulators, antibodies, immunoablativeagents, antibodies and/or antigen binding fragments thereof, antibodyconjugates, other antibody therapies, cytotoxins, steroids, cytokines,peptide vaccines, hormone therapy, antimetabolites, metabolicmodulators, drugs that inhibit either the calcium dependent phosphatasecalcineurin or the p70S6 kinase FK506) or inhibit the p70S6 kinase,alkylating agents, anthracyclines, vinca alkaloids, proteasomeinhibitors, GITR agonists, protein tyrosine phosphatase inhibitors,protein kinase inhibitors, an oncolytic virus, and/or other types ofimmunotherapy. In some embodiments, the additional agent or treatment isbone marrow transplantation, T cell ablative therapy using chemotherapyagents such as, fludarabine, external-beam radiation therapy (XRT),cyclophosphamide, and/or antibody therapy.

In some embodiments, the cells, binding molecules (e.g., BCMA-bindingmolecules), recombinant receptors and/or compositions, e.g.,CAR-expressing cells, are administered in combination with otherengineered cells, e.g., other CAR-expressing cells. In some embodiments,the additional agent is a kinase inhibitor, e.g., an inhibitor ofBruton's tyrosine kinase (Btk), e.g., ibrutinib. In some embodiments,the additional agent is an adenosine pathway or adenosine receptorantagonist or agonist. In some embodiments, the additional agent is animmunomodulator such as thalidomide or a thalidomide derivative (e.g.,lenalidomide). In some embodiments, the additional therapy, agent ortreatment is a cytotoxic or chemotherapy agent, a biologic therapy(e.g., antibody, e.g., monoclonal antibody, or cellular therapy), or aninhibitor (e.g., kinase inhibitor).

In some embodiments, a chemotherapeutic agent (sometimes referred to asa cytotoxic agent) is administered to the subject to disrupt a lesion.In certain embodiments, the lesion is tumor. In particular embodiments,the lesion is cancerous. In particular embodiments, the chemotherapeuticagent is any agent known to those of skill in the art to be effectivefor the treatment, prevention or amelioration of hyperproliferativedisorders such as cancer. Chemotherapeutic agents include, but are notlimited to, small molecules, synthetic drugs, peptides, polypeptides,proteins, nucleic acids (e.g., DNA and RNA polynucleotides including,but not limited to, antisense nucleotide sequences, triple helices andnucleotide sequences encoding biologically active proteins, polypeptidesor peptides), antibodies, synthetic or natural inorganic molecules,mimetic agents, and synthetic or natural organic molecules. Inparticular embodiments, chemotherapeutic drugs include alkylatingagents, anthracyclines, cytoskeletal disruptors (taxanes), epothilones,histone deacetylase inhibitors, topoisomerase inhibitors, topoisomeraseII inhibitors, kinase inhibitors, nucleotide analogs and precursoranalogs, peptide antibiotics, platinum-based agents, and vinca alkaloidsand derivatives.

In certain embodiments, a lesion is disrupted by administering achemotherapeutic agent to modulate genetically engineered cells in vivo.Chemotherapeutic agents may include, but are not limited to, abarelix,aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine,amifostine, anastrozole, arsenic trioxide, asparaginase, BCG live,bevaceizumab, bexarotene, bleomycin, bortezomib, busulfan, calusterone,camptothecin, capecitabine, carboplatin, carmustine, celecoxib,cetuximab, chlorambucil, cinacalcet, cisplatin, cladribine,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, darbepoetinalfa, daunorubicin, denileukin diftitox, dexrazoxane, docetaxel,doxorubicin, dromostanolone, Elliott's B solution, epirubicin, epoetinalfa, estramustine, etoposide, exemestane, filgrastim, floxuridine,fludarabine, fluorouracil, fulvestrant, gemcitabine, gemtuzumabozogamicin, gefitinib, goserelin, hydroxyurea, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib, interferon alfa-2a, interferonalfa-2b, irinotecan, letrozole, leucovorin, levamisole, lomustine,meclorethamine, megestrol, melphalan, mercaptopurine, mesna,methotrexate, methoxsalen, methylprednisolone, mitomycin C, mitotane,mitoxantrone, nandrolone, nofetumomab, oblimersen, oprelvekin,oxaliplatin, paclitaxel, pamidronate, pegademase, pegaspargase,pegfilgrastim, pemetrexed, pentostatin, pipobroman, plicamycin,polifeprosan, porfimer, procarbazine, quinacrine, rasburicase,rituximab, sargramostim, streptozocin, talc, tamoxifen, tarceva,temozolomide, teniposide, testolactone, thioguanine, thiotepa,topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracilmustard, valrubicin, vinblastine, vincristine, vinorelbine, andzoledronate.

In some embodiments, exemplary chemotherapeutic agents include ananthracycline (e.g., doxorubicin, such as liposomal doxorubicin); avinca alkaloid (e.g., vinblastine, vincristine, vindesine, vinorelbine);an alkylating agent (e.g., cyclophosphamide, decarbazine, melphalan,ifosfamide, temozolomide); an immune cell antibody (e.g., alemtuzumab,gemtuzumab, rituximab, tositumomab); an antimetabolite (including, e.g.,folic acid antagonists, pyrimidine analogs, purine analogs and adenosinedeaminase inhibitors such as fludarabine); a TNFR glucocorticoid inducedTNFR related protein (GITR) agonist; a proteasome inhibitor (e.g.,aclacinomycin A, gliotoxin or bortezomib); an immunomodulatory such asthalidomide or a thalidomide derivative (e.g., lenalidomide).

In some embodiments, the additional therapy or treatment is celltherapy, e.g., adoptive cell therapy. In some embodiments, theadditional therapy includes administration of engineered cells, e.g.,additional CAR-expressing cell. In some embodiments, the additionalengineered cell is a CAR-expressing cell that expresses the same ordifferent recombinant receptor as the engineered cells provided herein,e.g., anti-BCMA CAR-expressing cells. In some embodiments, therecombinant receptor, e.g., CAR, expressed on the additional engineeredcell, recognizes a different antigen and/or epitope. In someembodiments, the recombinant receptor, e.g., CAR, expressed on theadditional engineered cell, recognizes a different epitope of the sameantigen as the recombinant receptors described herein, e.g., BCMA. Insome embodiments, the recombinant receptor, e.g., CAR, expressed on theadditional engineered cell, recognizes a different antigen, e.g., adifferent tumor antigen or combination of antigens. For example, in someembodiments, the recombinant receptor, e.g., CAR, expressed on theadditional engineered cell, targets cancer cells that express earlylineage markers, e.g., cancer stem cells, while other CAR-expressingcells target cancer cells that express later lineage markers. In suchembodiments, the additional engineered cell is administered prior to,concurrently with, or after administration (e.g., infusion) of theCAR-expressing cells described herein. In some embodiments, theadditional engineered cell expresses allogeneic CAR.

In some embodiments, the configurations of one or more of the CARmolecules comprise a primary intracellular signaling domain and two ormore, e.g., 2, 3, 4, or 5 or more, costimulatory signaling domains. Insome embodiments, the one or more of the CAR molecules may have the sameor a different primary intracellular signaling domain, the same ordifferent costimulatory signaling domains, or the same number or adifferent number of costimulatory signaling domains. In someembodiments, the one or more of the CAR molecules can be configured as asplit CAR, in which one of the CAR molecules comprises an antigenbinding domain and a costimulatory domain (e.g., 4-1BB), while the otherCAR molecule comprises an antigen binding domain and a primaryintracellular signaling domain (e.g., CD3 zeta).

In some embodiments, the additional agent is any of the multispecificbinding molecules and/or cells engineered to express one or more of thebinding molecules described herein and/or cells engineered to expressadditional binding molecules, e.g., recombinant receptors, e.g., CAR,that target a different antigen. In some embodiments, the additionalagent includes any of the cells or plurality of cells described herein,e.g., in Section I.C. In some embodiments, the additional agent is acell engineered to express a recombinant receptor, e.g., CAR, targetinga different epitope and/or antigen, e.g., a different antigen associatedwith a disease or condition. In some embodiments, the additional agentis a cell engineered to express a recombinant receptor, e.g., CAR,targeting a second or additional antigen expressed in multiple myeloma,e.g., CD38, CD138, CS-1, BAFF-R, TACI and/or FcRH5.

In some embodiments, the additional agent is an immunomodulatory agent.In some embodiments, the combination therapy includes animmunomodulatory agent that can stimulate, amplify and/or otherwiseenhance an anti-tumor immune response, e.g. anti-tumor immune responsefrom the administered engineered cells, such as by inhibitingimmunosuppressive signaling or enhancing immunostimulant signaling. Insome embodiments, the immunomodulatory agent is a peptide, protein or isa small molecule. In some embodiments, the protein can be a fusionprotein or a recombinant protein. In some embodiments, theimmunomodulatory agent binds to an immunologic target, such as a cellsurface receptor expressed on immune cells, such a T cells, B cells orantigen-presenting cells. For example, in some embodiments, theimmunomodulatory agent is an antibody or antigen-binding antibodyfragment, a fusion protein, a small molecule or a polypeptide. In someembodiments, the binding molecules, recombinant receptors, cells and/orcompositions are administered in combination with an additional agentthat is an antibody or an antigen-binding fragment thereof, such as amonoclonal antibody.

In some embodiments, the immunomodulatory agent blocks, inhibits orcounteracts a component of the immune checkpoint pathway. The immunesystem has multiple inhibitory pathways that are involved in maintainingself-tolerance and for modulating immune responses. Tumors can usecertain immune-checkpoint pathways as a major mechanism of immuneresistance, particularly against T cells that are specific for tumorantigens (Pardoll (2012) Nature Reviews Cancer 12:252-264), e.g.,engineered cells such as CAR-expressing cells. Because many such immunecheckpoints are initiated by ligand-receptor interactions, they can bereadily blocked by antibodies against the ligands and/or theirreceptors.

Therefore, therapy with antagonistic molecules blocking an immunecheckpoint pathway, such as small molecules, nucleic acid inhibitors(e.g., RNAi) or antibody molecules, are becoming promising avenues ofimmunotherapy for cancer and other diseases. In contrast to the majorityof anti-cancer agents, checkpoint inhibitors do not necessarily targettumor cells directly, but rather target lymphocyte receptors or theirligands in order to enhance the endogenous antitumor activity of theimmune system.

As used herein, the term “immune checkpoint inhibitor” refers tomolecules that totally or partially reduce, inhibit, interfere with ormodulate one or more checkpoint proteins. Checkpoint proteins regulateT-cell activation or function. These proteins are responsible forco-stimulatory or inhibitory interactions of T-cell responses. Immunecheckpoint proteins regulate and maintain self-tolerance and theduration and amplitude of physiological immune responses. In someembodiments, the subject can be administered an additional agent thatcan enhance or boost the immune response, e.g., immune response effectedby the binding molecules (e.g., BCMA-binding molecules), recombinantreceptors, cells and/or compositions provided herein, against a diseaseor condition, e.g., a cancer, such as any described herein.

Immune checkpoint inhibitors include any agent that blocks or inhibitsin a statistically significant manner, the inhibitory pathways of theimmune system. Such inhibitors may include small molecule inhibitors ormay include antibodies, or antigen binding fragments thereof, that bindto and block or inhibit immune checkpoint receptors, ligands and/orreceptor-ligand interaction. In some embodiments, modulation,enhancement and/or stimulation of particular receptors can overcomeimmune checkpoint pathway components. Illustrative immune checkpointmolecules that may be targeted for blocking, inhibition, modulation,enhancement and/or stimulation include, but are not limited to, PD-1(CD279), PD-L1 (CD274, B7-H1), PDL2 (CD273, B7-DC), CTLA-4, LAG-3(CD223), TIM-3, 4-1BB (CD137), 4-1BBL (CD137L), GITR (TNFRSF18, AITR),CD40, OX₄₀ (CD134, TNFRSF4), CXCR2, tumor associated antigens (TAA),B7-H3, B7-H4, BTLA, HVEM, GAL9, B7H3, B7H4, VISTA, KIR, 2B4 (belongs tothe CD2 family of molecules and is expressed on all NK, γδ, and memoryCD8+(αβ) T cells), CD160 (also referred to as BY55), CGEN-15049, CEACAM(e.g., CEACAM-1, CEACAM-3 and/or CEACAM-5), TIGIT, LAIR1, CD160, 2B4,CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR,A2aR, MHC class I, MHC class II, GAL9, adenosine, and a transforminggrowth factor receptor (TGFR; e.g., TGFR beta). Immune checkpointinhibitors include antibodies, or antigen binding fragments thereof, orother binding proteins that bind to and block or inhibit and/or enhanceor stimulate the activity of one or more of any of the said molecules.

Exemplary immune checkpoint inhibitors include Tremelimumab (CTLA-4blocking antibody, also known as ticilimumab, CP-675,206), anti-0X₄₀,PD-L1 monoclonal antibody (Anti-B7-H1; MEDI4736), MK-3475 (PD-1blocker), nivolumab (anti-PD-1 antibody), CT-011 (anti-PD-1 antibody),BY55 monoclonal antibody, AMP224 (anti-PD-L1 antibody), BMS-936559(anti-PD-L1 antibody), MPLDL3280A (anti-PD-L1 antibody), MSB0010718C(anti-PD-L1 antibody) and ipilimumab (anti-CTLA-4 antibody, also knownas Yervoy®, MDX-010 and MDX-101). Exemplary of immunomodulatoryantibodies include, but are not limited to, Daclizumab (Zenapax),Bevacizumab (Avastin C)), Basiliximab, Ipilimumab, Nivolumab,pembrolizumab, MPDL3280A, Pidilizumab (CT-011), MK-3475, BMS-936559,MPDL3280A (Atezolizumab), tremelimumab, IMP321, BMS-986016, LAG525,urelumab, PF-05082566, TRX518, MK-4166, dacetuzumab (SGN-40),lucatumumab (HCD122), SEA-CD40, CP-870, CP-893, MEDI6469, MEDI6383,MOXR0916, AMP-224, MSB0010718C (Avelumab), MEDI4736, PDR001, rHIgM12B7,Ulocuplumab, BKT140, Varlilumab (CDX-1127), ARGX-110, MGA271, lirilumab(BMS-986015, IPH2101), IPH2201, ARGX-115, Emactuzumab, CC-90002 andMNRP1685A or an antibody-binding fragment thereof. Other exemplaryimmunomodulators include, e.g., afutuzumab (available from Roche®);pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®);thalidomide (Thalomid®), actimid (CC4047); and IRX-2 (mixture of humancytokines including interleukin 1, interleukin 2, and interferon.gamma.,CAS 951209-71-5, available from IRX Therapeutics).

Programmed cell death 1 (PD-1) is an immune checkpoint protein that isexpressed in B cells, NK cells, and T cells (Shinohara et al., 1995,Genomics 23:704-6; Blank et al., 2007, Cancer Immunol Immunother56:739-45; Finger et al., 1997, Gene 197:177-87; Pardoll (2012) NatureReviews Cancer 12:252-264). The major role of PD-1 is to limit theactivity of T cells in peripheral tissues during inflammation inresponse to infection, as well as to limit autoimmunity. PD-1 expressionis induced in activated T cells and binding of PD-1 to one of itsendogenous ligands acts to inhibit T-cell activation by inhibitingstimulatory kinases. PD-1 also acts to inhibit the TCR “stop signal”.PD-1 is highly expressed on Treg cells and may increase theirproliferation in the presence of ligand (Pardoll (2012) Nature ReviewsCancer 12:252-264). Anti-PD 1 antibodies have been used for treatment ofmelanoma, non-small-cell lung cancer, bladder cancer, prostate cancer,colorectal cancer, head and neck cancer, triple-negative breast cancer,leukemia, lymphoma and renal cell cancer (Topalian et al., 2012, N EnglJ Med 366:2443-54; Lipson et al., 2013, Clin Cancer Res 19:462-8; Bergeret al., 2008, Clin Cancer Res 14:3044-51; Gildener-Leapman et al., 2013,Oral Oncol 49:1089-96; Menzies & Long, 2013, Ther Adv Med Oncol5:278-85). Exemplary anti-PD-1 antibodies include nivolumab (Opdivo byBMS), pembrolizumab (Keytruda by Merck), pidilizumab (CT-011 by CureTech), lambrolizumab (MK-3475 by Merck), and AMP-224 (Merck), nivolumab(also referred to as Opdivo, BMS-936558 or MDX1106; Bristol-MyersSquibb) is a fully human IgG4 monoclonal antibody which specificallyblocks PD-1. Nivolumab (clone 5C4) and other human monoclonal antibodiesthat specifically bind to PD-1 are described in U.S. Pat. No. 8,008,449and WO2006/121168. Pidilizumab (CT-011; Cure Tech) is a humanized IgGlkmonoclonal antibody that binds to PD-1. Pidilizumab and other humanizedanti-PD-1 monoclonal antibodies are described in WO2009/101611.Pembrolizumab (formerly known as lambrolizumab, and also referred to asKeytruda, MK03475; Merck) is a humanized IgG4 monoclonal antibody thatbinds to PD-1. Pembrolizumab and other humanized anti-PD-1 antibodiesare described in U.S. Pat. No. 8,354,509 and WO2009/114335. Otheranti-PD-1 antibodies include AMP 514 (Amplimmune), among others, e.g.,anti-PD-1 antibodies described in U.S. Pat. No. 8,609,089, US2010028330, US 20120114649 and/or US 20150210769. AMP-224 (B7-DCIg;Amplimmune; e.g., described in WO2010/027827 and WO2011/066342), is aPD-L2 Fc fusion soluble receptor that blocks the interaction betweenPD-1 and B7-H1.

PD-L1 (also known as CD274 and B7-H1) and PD-L2 (also known as CD273 andB7-DC) are ligands for PD-1, found on activated T cells, B cells,myeloid cells, macrophages, and some types of tumor cells. Anti-tumortherapies have focused on anti-PD-L1 antibodies. The complex of PD-1 andPD-L1 inhibits proliferation of CD8+ T cells and reduces the immuneresponse (Topalian et al., 2012, N Engl J Med 366:2443-54; Brahmer etal., 2012, N Eng J Med 366:2455-65). Anti-PD-L1 antibodies have beenused for treatment of non-small cell lung cancer, melanoma, colorectalcancer, renal-cell cancer, pancreatic cancer, gastric cancer, ovariancancer, breast cancer, and hematologic malignancies (Brahmer et al.,2012, N Eng J Med 366:2455-65; Ott et al., 2013, Clin Cancer Res19:5300-9; Radvanyi et al., 2013, Clin Cancer Res 19:5541; Menzies &Long, 2013, Ther Adv Med Oncol 5:278-85; Berger et al., 2008, ClinCancer Res 14:13044-51). Exemplary anti-PD-L1 antibodies includeMDX-1105 (Medarex), MEDI4736 (Medimmune) MPDL3280A (Genentech),BMS-935559 (Bristol-Myers Squibb) and MSB0010718C. MEDI4736 (Medimmune)is a human monoclonal antibody that binds to PD-L1, and inhibitsinteraction of the ligand with PD-1. MDPL3280A (Genentech/Roche) is ahuman Fc optimized IgG1 monoclonal antibody that binds to PD-L1.MDPL3280A and other human monoclonal antibodies to PD-L1 are describedin U.S. Pat. No. 7,943,743 and U.S Publication No. 20120039906. Otheranti-PD-L1 binding agents include YW243.55.570 (see WO2010/077634) andMDX-1105 (also referred to as BMS-936559, and, e.g., anti-PD-L1 bindingagents described in WO2007/005874).

Cytotoxic T-lymphocyte-associated antigen (CTLA-4), also known as CD152,is a co-inhibitory molecule that functions to regulate T-cellactivation. CTLA-4 is a member of the immunoglobulin superfamily that isexpressed exclusively on T-cells. CTLA-4 acts to inhibit T-cellactivation and is reported to inhibit helper T-cell activity and enhanceregulatory T-cell immunosuppressive activity. Although the precisemechanism of action of CTLA-4 remains under investigation, it has beensuggested that it inhibits T cell activation by outcompeting CD28 inbinding to CD80 and CD86, as well as actively delivering inhibitorsignals to the T cell (Pardoll (2012) Nature Reviews Cancer 12:252-264).Anti-CTLA-4 antibodies have been used in clinical trials for thetreatment of melanoma, prostate cancer, small cell lung cancer,non-small cell lung cancer (Robert & Ghiringhelli, 2009, Oncologist14:848-61; Ott et al., 2013, Clin Cancer Res 19:5300; Weber, 2007,Oncologist 12:864-72; Wada et al., 2013, J Transl Med 11:89). Asignificant feature of anti-CTLA-4 is the kinetics of anti-tumor effect,with a lag period of up to 6 months after initial treatment required forphysiologic response. In some cases, tumors may actually increase insize after treatment initiation, before a reduction is seen (Pardoll(2012) Nature Reviews Cancer 12:252-264). Exemplary anti-CTLA-4antibodies include ipilimumab (Bristol-Myers Squibb) and tremelimumab(Pfizer). Ipilimumab has recently received FDA approval for treatment ofmetastatic melanoma (Wada et al., 2013, J Transl Med 11:89).

Lymphocyte activation gene-3 (LAG-3), also known as CD223, is anotherimmune checkpoint protein. LAG-3 has been associated with the inhibitionof lymphocyte activity and in some cases the induction of lymphocyteanergy. LAG-3 is expressed on various cells in the immune systemincluding B cells, NK cells, and dendritic cells. LAG-3 is a naturalligand for the MHC class II receptor, which is substantially expressedon melanoma-infiltrating T cells including those endowed with potentimmune-suppressive activity. Exemplary anti-LAG-3 antibodies includeBMS-986016 (Bristol-Myers Squib), which is a monoclonal antibody thattargets LAG-3. IMP701 (Immutep) is an antagonist LAG-3 antibody andIMP731 (Immutep and GlaxoSmithKline) is a depleting LAG-3 antibody.Other LAG-3 inhibitors include IMP321 (Immutep), which is a recombinantfusion protein of a soluble portion of LAG-3 and Ig that binds to MHCclass II molecules and activates antigen presenting cells (APC). Otherantibodies are described, e.g., in WO2010/019570 and US 2015/0259420

T-cell immunoglobulin domain and mucin domain-3 (TIM-3), initiallyidentified on activated Th1 cells, has been shown to be a negativeregulator of the immune response. Blockade of TIM-3 promotes T-cellmediated anti-tumor immunity and has anti-tumor activity in a range ofmouse tumor models. Combinations of TIM-3 blockade with otherimmunotherapeutic agents such as TSR-042, anti-CD137 antibodies andothers, can be additive or synergistic in increasing anti-tumor effects.TIM-3 expression has been associated with a number of different tumortypes including melanoma, NSCLC and renal cancer, and additionally,expression of intratumoral TIM-3 has been shown to correlate with poorprognosis across a range of tumor types including NSCLC, cervical, andgastric cancers. Blockade of TIM-3 is also of interest in promotingincreased immunity to a number of chronic viral diseases. TIM-3 has alsobeen shown to interact with a number of ligands including galectin-9,phosphatidylserine and HMGB1, although which of these, if any, arerelevant in regulation of anti-tumor responses is not clear at present.In some embodiments, antibodies, antibody fragments, small molecules, orpeptide inhibitors that target TIM-3 can bind to the IgV domain of TIM-3to inhibit interaction with its ligands. Exemplary antibodies andpeptides that inhibit TIM-3 are described in US 2015/0218274,WO2013/006490 and US 2010/0247521. Other anti-TIM-3 antibodies includehumanized versions of RMT3-23 (Ngiow et al., 2011, Cancer Res,71:3540-3551), and clone 8B.2C12 (Monney et al., 2002, Nature,415:536-541). Bi-specific antibodies that inhibit TIM-3 and PD-1 aredescribed in US 2013/0156774.

In some embodiments, the additional agent is a CEACAM inhibitor (e.g.,CEACAM-1, CEACAM-3, and/or CEACAM-5 inhibitor). In some embodiments, theinhibitor of CEACAM is an anti-CEACAM antibody molecule. Exemplaryanti-CEACAM-1 antibodies are described in WO 2010/125571, WO 2013/082366WO 2014/059251 and WO 2014/022332, e.g., a monoclonal antibody 34B1,26H7, and 5F4; or a recombinant form thereof, as described in, e.g., US2004/0047858, U.S. Pat. No. 7,132,255 and WO 99/052552. In someembodiments, the anti-CEACAM antibody binds to CEACAM-5 as described in,e.g., Zheng et al. PLoS One. (2011) 6(6): e21146), or cross-reacts withCEACAM-1 and CEACAM-5 as described in, e.g., WO 2013/054331 and US2014/0271618.

4-1BB, also known as CD137, is transmembrane glycoprotein belonging tothe TNFR superfamily. 4-1BB receptors are present on activated T cellsand B cells and monocytes. An exemplary anti-4-1BB antibody is urelumab(BMS-663513), which has potential immunostimulatory and antineoplasticactivities.

Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4), alsoknown as OX40 and CD134, is another member of the TNFR superfamily. 0X₄₀is not constitutively expressed on resting naïve T cells and acts as asecondary co-stimulatory immune checkpoint molecule. Exemplary anti-OX40antibodies are MEDI6469 and MOXR0916 (RG7888, Genentech).

In some embodiments, the additional agent includes a molecule thatdecreases the regulatory T cell (Treg) population. Methods that decreasethe number of (e.g., deplete) Treg cells are known in the art andinclude, e.g., CD25 depletion, cyclophosphamide administration, andmodulating Glucocorticoid-induced TNFR family related gene (GITR)function. GITR is a member of the TNFR superfamily that is upregulatedon activated T cells, which enhances the immune system. Reducing thenumber of Treg cells in a subject prior to apheresis or prior toadministration of engineered cells, e.g., CAR-expressing cells, canreduce the number of unwanted immune cells (e.g., Tregs) in the tumormicroenvironment and reduces the subject's risk of relapse. In someembodiments, the additional agent includes a molecule targeting GITRand/or modulating GITR functions, such as a GITR agonist and/or a GITRantibody that depletes regulatory T cells (Tregs). In some embodiments,the additional agent includes cyclophosphamide. In some embodiments, theGITR binding molecule and/or molecule modulating GITR function (e.g.,GITR agonist and/or Treg depleting GITR antibodies) is administeredprior to the engineered cells, e.g., CAR-expressing cells. For example,in some embodiments, the GITR agonist can be administered prior toapheresis of the cells. In some embodiments, cyclophosphamide isadministered to the subject prior to administration (e.g., infusion orre-infusion) of the engineered cells, e.g., CAR-expressing cells orprior to apheresis of the cells. In some embodiments, cyclophosphamideand an anti-GITR antibody are administered to the subject prior toadministration (e.g., infusion or re-infusion) of the engineered cells,e.g., CAR-expressing cells or prior to apheresis of the cells.

In some embodiments, the additional agent is a GITR agonist. ExemplaryGITR agonists include, e.g., GITR fusion proteins and anti-GITRantibodies (e.g., bivalent anti-GITR antibodies) such as, e.g., a GITRfusion protein described in U.S. Pat. No. 6,111,090, European Patent No.090505B 1, U.S. Pat. No. 8,586,023, PCT Publication Nos.: WO 2010/003118and 2011/090754, or an anti-GITR antibody described, e.g., in U.S. Pat.No. 7,025,962, European Patent No. 1947183B 1, U.S. Pat. Nos. 7,812,135,8,388,967, 8,591,886, European Patent No. EP 1866339, PCT PublicationNo. WO 2011/028683, PCT Publication No. WO 2013/039954, PCT PublicationNo. WO2005/007190, PCT Publication No. WO 2007/133822, PCT PublicationNo. WO2005/055808, PCT Publication No. WO 99/40196, PCT Publication No.WO 2001/03720, PCT Publication No. WO99/20758, PCT Publication No.WO2006/083289, PCT Publication No. WO 2005/115451, U.S. Pat. No.7,618,632, and PCT Publication No. WO 2011/051726. An exemplaryanti-GITR antibody is TRX518.

In some embodiments, the additional agent enhances tumor infiltration ortransmigration of the administered cells, e.g., CAR-expressing cells.For example, in some embodiments, the additional agent stimulates CD40,such as CD40L, e.g., recombinant human CD40L. Cluster of differentiation40 (CD40) is also a member of the TNFR superfamily. CD40 is acostimulatory protein found on antigen-presenting cells and mediates abroad variety of immune and inflammatory responses. CD40 is alsoexpressed on some malignancies, where it promotes proliferation.Exemplary anti-CD40 antibodies are dacetuzumab (SGN-40), lucatumumab(Novartis, antagonist), SEA-CD40 (Seattle Genetics), and CP-870,893. Insome embodiments, the additional agent that enhances tumor infiltrationincludes tyrosine kinase inhibitor sunitnib, heparanase, and/orchemokine receptors such as CCR2, CCR4, and CCR7.

In some embodiments, the additional agent is a structural or functionalanalog or derivative of thalidomide and/or an inhibitor of E3 ubiquitinligase. In some embodiments, the immunomodulatory agent binds tocereblon (CRBN). In some embodiments, the immunomodulatory agent bindsto the CRBN E3 ubiquitin-ligase complex. In some embodiments, theimmunomodulatory agent binds to CRBN and the CRBN E3 ubiquitin-ligasecomplex. In some embodiments, the immunomodulatory agent up-regulatesthe protein or gene expression of CRBN. In some aspects, CRBN is thesubstrate adaptor for the CRL4^(CRBN) E3 ubiquitin ligase, and modulatesthe specificity of the enzyme. In some embodiments, binding to CRB orthe CRBN E3 ubiquitin ligase complex inhibits E3 ubiquitin ligaseactivity. In some embodiments, the immunomodulatory agent induces theubiquitination of KZF1 (Ikaros) and IKZF3 (Aiolos) and/or inducesdegradation of IKZF1 (Ikaros) and IKZF3 (Aiolos). In some embodiments,the immunomodulatory agent induces the ubiquitination of casein kinase1A1 (CK1α) by the CRL4^(CRBN) E3 ubiquitin ligase. In some embodiments,the ubiquitination of CK1α results in CK1α degradation.

In some embodiments, the additional agent is an inhibitor of the Ikaros(IKZF1) transcription factor. In some embodiments, the additional agentenhances ubiquitination of Ikaros. In some embodiments, the additionalagent enhances the degradation of Ikaros. In some embodiments, theadditional agent down-regulates the protein or gene expression ofIkaros. In some embodiments, administration of the additional agentcauses a decrease in Ikaros protein levels.

In some embodiments, the additional agent is an inhibitor of the Aiolos(IKZF3) transcription factor. In some embodiments, the additional agentenhances ubiquitination of Aiolos. In some embodiments, the additionalagent enhances the degradation of Aiolos. In some embodiments, theadditional agent down-regulates the protein or gene expression ofAiolos. In some embodiments, administration of the additional agentcauses a decrease in Aiolos protein levels.

In some embodiments, the additional agent is an inhibitor of both theIkaros (IKZF1) and Aiolos (IKZF3) transcription factors. In someembodiments, the additional agent enhances ubiquitination of both Ikarosand Aiolos. In some embodiments, the additional agent enhances thedegradation of both Ikaros and Aiolos. In some embodiments, theadditional agent enhances ubiquitination and degradation of both Ikarosand Aiolos. In some embodiments, administration of the additional agentcauses both Aiolos protein levels and Ikaros protein levels to decrease.

In some embodiments, the additional agent is a selective cytokineinhibitory drug (SelCID). In some embodiments, the additional agentinhibits the activity of phosphodiesterase-4 (PDE4). In someembodiments, the additional agent suppresses the enzymatic activity ofthe CDC25 phosphatases. In some embodiments, the additional agent altersthe intracellular trafficking of CDC25 phosphatases.

In some embodiments, the additional agent is thalidomide(2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione) or an analog orderivative of thalidomide. In certain embodiments, a thalidomidederivative includes structural variants of thalidomide that have asimilar biological activity. Exemplary thalidomide derivatives include,but are not limited to lenalidomide (REVLIMMUNOMODULATORY COMPOUND™;Celgene Corporation), pomalidomide (also known as ACTIMMUNOMODULATORYCOMPOUND™ or POMALYST™ (Celgene Corporation)), CC-1088, CDC-501, andCDC-801, and the compounds disclosed in U.S. Pat. Nos. 5,712,291;7,320,991; and 8,716,315; U.S. Appl. No. 2016/0313300; and PCT Pub. Nos.WO 2002/068414 and WO 2008/154252.

In some embodiments, the additional agent is 1-oxo- and 1,3dioxo-2-(2,6-dioxopiperldin-3-yl) isoindolines substituted with amino inthe benzo ring as described in U.S. Pat. No. 5,635,517 which isincorporated herein by reference.

In some embodiments, the additional agent is a compound of the followingformula:

-   -   wherein one of X and Y is —C(O)— and the other of X and Y is        —C(O)— or —CH₂—, and R⁵ is hydrogen or lower alkyl, or a        pharmaceutically acceptable salt thereof. In some embodiments, X        is —C(O)— and Y is —CH₂—. In some embodiments, both X and Y are        —C(O)—. In some embodiments, R⁵ is hydrogen. In other        embodiments, R⁵ is methyl.

In some embodiments, the additional agent is a compound that belongs toa class of substituted 2-(2, 6-dioxopiperidin-3-yl)phthalateimmunomodulatory compounds and substituted2-(2,6-dioxopiperldin-3-yl)-1-oxoisoindoles, such as those described inU.S. Pat. Nos. 6,281,230; 6,316,471; 6,335,349; and 6,476,052, andInternational Patent Application No. PCT/US97/13375 (InternationalPublication No. WO 98/03502), each of which is incorporated herein byreference.

In some embodiments, the additional agent is a compound of the followingformula:

-   -   wherein    -   one of X and Y is —C(O)— and the other of X and Y is —C(O)— or        —CH₂—;    -   (1) each of R¹, R², R³, and R⁴ are independently halo, alkyl of        1 to 4 carbon atoms, or alkoxy or 1 to 4 carbon atoms, or    -   (2) one of R¹, R³, R⁴, and R⁵ is —NHR^(a) and the remaining of        R², R³, and R⁴ is are hydrogen, wherein R^(a) is hydrogen or        alkyl of 1 to 8 carbon atoms;    -   R⁵ is hydrogen or alkyl of 1 to 8 carbon atoms, benzyl, or halo;    -   provided that R⁵ is other than hydrogen if X and Y are —C(O)—        and (i) each of R¹, R², R³, and R⁴ is fluoro; or (ii) one of R¹,        R², R³, and R⁴ is amino;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments, the additional agent is a compound that belongs toa class of isoindole-immunomodulatory compounds disclosed in U.S. Pat.No. 7,091,353, U.S. Patent Publication No. 2003/0045552, andInternational Application No. PCT/USOI/50401 (International PublicationNo. WO02/059106), each of which are incorporated herein by reference.For example, in some embodiments, the additional agent is[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide;(2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl)-carbamicacid tert-butyl ester;4-(aminomethyl)-2-(2,6-dioxo(3-piperidyl)-isoindoline-1,3-dione;N-(2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl)-acetamide;N-{(2-(2,6-dioxo(3-piperidyl)-1,3-dioxoisoindolin-4-yl)methyl}cyclopropyl-carboxamide;2-chloro-N-{(2-(2,6-dioxo(3-piperidyl)-1,3-dioxoisoindolin-4-yl)methyl}acetamide;N-(2-(2,6-dioxo(3-piperidyl)-1,3-dioxoisoindolin-4-yl)-3-pyridylcarboxamide;3-[1-oxo-4-(benzylamino)isoindolin-2-yl]piperidine-2,6-dione;2-(2,6-dioxo(3-piperidyl)-4-(benzylamino)isoindoline-1,3-dione;N-{(2-(2,6-dioxo(3-piperidyl)-1,3-dioxoisoindolin-4-yl)methyl}propanamide;N-{(2-(2,6-dioxo(3-piperidyl)-1,3-dioxoisoindolin-4-yl)methyl}-3-pyridylcarboxamide;N-{(2-(2,6-dioxo(3-piperidyl)-1,3-dioxoisoindolin-4-yl)methyl}heptanamide;N-{(2-(2,6-dioxo(3-piperidyl)-1,3-dioxoisoindolin-4-yl)methyl}-2-furylcarboxamide;{N-(2-(2,6-dioxo(3-piperidyl)-1,3-dioxoisoindolin-4-yl)carbamoyl}methylacetate;N-(2-(2,6-dioxo(3-piperidyl)-1,3-dioxoisoindolin-4-yl)pentanamide;N-(2-(2,6-dioxo(3-piperidyl)-1,3-dioxoisoindolin-4-yl)-2-thienylcarboxamide;N-{[2-(2,6-dioxo(3-piperidyl)-1,3-dioxoisoindolin-4-yl]methyl}(butylamino)carboxamide;N-{[2-(2,6-dioxo(3-piperidyl)-1,3-dioxoisoindolin-4-yl]methyl}(octylamino)carboxamide;or N-{[2-(2,6-dioxo(3-piperidyl))-1,3-dioxoisoindolin-4-yl]methyl}(benzylamino)carboxamide.

In some embodiments, the additional agent is a compound that belongs toa class of isoindole-immunomodulatory compounds disclosed in U.S. PatentApplication Publication Nos. 2002/0045643, International Publication No.WO 98/54170, and U.S. Pat. No. 6,395,754, each of which is incorporatedherein by reference. In some embodiments, the additional agent is atetra substituted 2-(2,6-dioxopiperdin-3-yl)-1-oxoisoindolines describedin U.S. Pat. No. 5,798,368, which is incorporated herein by reference.In some embodiments, the additional agent is 1-oxo and1,3-dioxo-2-(2,6-dioxopiperidin-3-yl) isoindolines disclosed in U.S.Pat. No. 6,403,613, which is incorporated herein by reference. In someembodiments the additional agent is a 1-oxo or 1,3-dioxoisoindolinesubstituted in the 4- or 5-position of the indoline ring as described inU.S. Pat. Nos. 6,380,239 and 7,244,759, both of which are incorporatedherein by reference.

In some embodiments, the additional agent is2-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-4-carbamoyl-butyric acid or4-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-4-carbamoyl-butyric acid. Insome embodiments, the immunomodulatory compound is4-carbamoyl-4-{4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}-butyricacid,4-carbamoyl-2-{4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}-butyricacid,2-{4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}-4-phenylcarbamoyl-butyricacid, or2-{4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}-pentanedioicacid.

In some embodiments, the additional agent is a isoindoline-1-one orisoindoline-1,3-dione substituted in the 2-position with2,6-dioxo-3-hydroxypiperidin-5-yl as described in U.S. Pat. No.6,458,810, which is incorporated herein by reference. In someembodiments, the immunomodulatory compound is3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione, oran enantiomer or a mixture of enantiomers thereof or a pharmaceuticallyacceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorphthereof. In some embodiments, the immunomodulatory compound is3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6-dione.

In some embodiments, the additional agent is as described in Oshima, K.et al., Nihon Rinsho., 72(6):1130-5 (2014); Millrine, D. et al., TrendsMol Med., 23(4):348-364 (2017); and Collins, et al., Biochem J.,474(7):1127-1147 (2017).

In some embodiments, the additional agent is lenalidomide, pomalidomide,avadomide, a stereoisomer of lenalidomide, pomalidomide, avadomide or apharmaceutically acceptable salt, solvate, hydrate, co-crystal,clathrate, or polymorph thereof. In some embodiments, theimmunomodulatory compound is lenalidomide, a stereoisomer oflenalidomide or a pharmaceutically acceptable salt, solvate, hydrate,co-crystal, clathrate, or polymorph thereof. In some embodiments, theimmunomodulatory compound is lenalidomide, or((RS)-3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione).

In certain embodiments, the lesion is disrupted by administering thethalidomide derivative lenalidomide,((RS)-3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione)to the subject. Lenalidomide is FDA approved for the treatment ofmultiple myeloma, myelodysplastic syndrome associated with deletion 5q,and most recently in relapsed/refractory mantle-cell lymphoma (MCL).Lenalidomide generally is a synthetic derivative of thalidomide, and iscurrently understood to have multiple immunomodulatory effects,including enforcement of immune synapse formation between T cell andantigen presenting cells (APCs). For example, in some cases,lenalidomide modulates T cell responses and results in increasedinterleukin (IL)-2 production in CD4⁺ and CD8⁺ T cells, induces theshift of T helper (Th) responses from Th2 to Th1, inhibits expansion ofregulatory subset of T cells (Tregs), and improves functioning ofimmunological synapses in follicular lymphoma and chronic lymphocyticleukemia (CLL) (Otahal et al., Oncoimmunology (2016) 5(4):e1115940).Lenalidomide also has direct tumoricidal activity in patients withmultiple myeloma (MM) and directly and indirectly modulates survival ofCLL tumor cells by affecting supportive cells, such as nurse-like cellsfound in the microenvironment of lymphoid tissues. Lenalidomide also canenhance T-cell proliferation and interferon-γ production in response toactivation of T cells via CD3 ligation or dendritic cell-mediatedactivation. In addition, lenalidomide is thought to decreaseproliferation of pro-inflammatory cytokines including TNF-α, IL-1, IL-6,and IL-12 and enhance antibody-dependent cellular cytotoxicity (ADCC)via increased NK cell activation. Lenalidomide can also induce malignantB cells to express higher levels of immunostimulatory molecules such asCD80, CD86, HLA-DR, CD95, and CD40 (Fecteau et al., Blood (2014)124(10):1637-1644). Cereblon, an E3 ubiquitin ligase, was identified asthe primary target for thalidomide-induced teratogenesis (Ito et al.,T., (2010) Science 327: 1345-1350). Lenalidomide also targets cereblonand it has been shown that this leads to the reduction of c-Myc and IRF4expression while also increasing expression of p21 that leads to G1cell-cycle arrest (Lopez-Girona et al., (2012) Leukemia 26: 2326-2335).

In some embodiments, the additional agent includes thalidomide drugs oranalogs thereof and/or derivatives thereof, such as lenalidomide,pomalidomide or apremilast. See, e.g., Bertilaccio et al., Blood (2013)122:4171, Otahal et al., Oncoimmunology (2016) 5(4):e1115940; Fecteau etal., Blood (2014) 124(10):1637-1644 and Kuramitsu et al., Cancer GeneTherapy (2015) 22:487-495). Lenalidomide((RS)-3-(4-Amino-1-oxo-1,3-dihydro-2H-isoindol-2-yOpiperidine-2,6-dione;also known as Revlimid) is a synthetic derivative of thalidomide, andhas multiple immunomodulatory effects, including enforcement of immunesynapse formation between T cell and antigen presenting cells (APCs).For example, in some cases, lenalidomide modulates T cell responses andresults in increased interleukin (IL)-2 production in CD4+ and CD8+ Tcells, induces the shift of T helper (Th) responses from Th2 to Th1,inhibits expansion of regulatory subset of T cells (Tregs), and improvesfunctioning of immunological synapses in follicular lymphoma and chroniclymphocytic leukemia (CLL) (Otahal et al., Oncoimmunology (2016)5(4):e1115940). Lenalidomide also has direct tumoricidal activity inpatients with multiple myeloma (MM) and directly and indirectlymodulates survival of CLL tumor cells by affecting supportive cells,such as nurse-like cells found in the microenvironment of lymphoidtissues. Lenalidomide also can enhance T-cell proliferation andinterferon-γ production in response to activation of T cells via CD3ligation or dendritic cell-mediated activation. Lenalidomide can alsoinduce malignant B cells to express higher levels of immunostimulatorymolecules such as CD80, CD86, HLA-DR, CD95, and CD40 (Fecteau et al.,Blood (2014) 124(10):1637-1644).

In some embodiments, the additional agent is a B-cell inhibitor. In someembodiments, the additional agent is one or more B-cell inhibitorsselected from among inhibitors of CD10, CD19, CD20, CD22, CD34, CD123,CD79a, CD79b, CD179b, FLT-3, or ROR1, or a combination thereof. In someembodiments, the B-cell inhibitor is an antibody (e.g., a mono- orbispecific antibody) or an antigen binding fragment thereof. In someembodiments, the additional agent is an engineered cell expressingrecombinant receptors that target B-cell targets, e.g., CD10, CD19,CD20, CD22, CD34, CD123, CD79a, CD79b, CD179b, FLT-3, or ROR1.

In some embodiments, the additional agent is a CD20 inhibitor, e.g., ananti-CD20 antibody (e.g., an anti-CD20 mono- or bi-specific antibody) ora fragment thereof. Exemplary anti-CD20 antibodies include but are notlimited to rituximab, ofatumumab, ocrelizumab (also known as GA101 orR05072759), veltuzumab, obinutuzumab, TRU-015 (Trubion Pharmaceuticals),ocaratuzumab (also known as AME-133v or ocaratuzumab), and Pro131921(Genentech). See, e.g., Lim et al. Haematologica. (2010) 95(1):135-43.In some embodiments, the anti-CD20 antibody comprises rituximab.Rituximab is a chimeric mouse/human monoclonal antibody IgG1 kappa thatbinds to CD20 and causes cytolysis of a CD20 expressing cell. In someembodiments, the additional agent includes rituximab. In someembodiments, the CD20 inhibitor is a small molecule.

In some embodiments, the additional agent is a CD22 inhibitor, e.g., ananti-CD22 antibody (e.g., an anti-CD22 mono- or bi-specific antibody) ora fragment thereof. Exemplary anti-CD22 antibodies include epratuzumaband RFB4. In some embodiments, the CD22 inhibitor is a small molecule.In some embodiments, the antibody is a monospecific antibody, optionallyconjugated to a second agent such as a chemotherapeutic agent. Forinstance, in some embodiments, the antibody is an anti-CD22 monoclonalantibody-MMAE conjugate (e.g., DCDT2980S). In some embodiments, theantibody is an scFv of an anti-CD22 antibody, e.g., an scFv of antibodyRFB4. In some embodiments, the scFv is fused to all of or a fragment ofPseudomonas exotoxin-A (e.g., BL22). In some embodiments, the scFv isfused to all of or a fragment of (e.g., a 38 kDa fragment of)Pseudomonas exotoxin-A (e.g., moxetumomab pasudotox). In someembodiments, the anti-CD22 antibody is an anti-CD19/CD22 bispecificantibody, optionally conjugated to a toxin. For instance, in someembodiments, the anti-CD22 antibody comprises an anti-CD19/CD22bispecific portion, (e.g., two scFv ligands, recognizing human CD19 andCD22) optionally linked to all of or a portion of diphtheria toxin (DT),e.g., first 389 amino acids of diphtheria toxin (DT), DT 390, e.g., aligand-directed toxin such as DT2219ARL). In some embodiments, thebispecific portion (e.g., anti-CD 19/anti-CD22) is linked to a toxinsuch as deglycosylated ricin A chain (e.g., Combotox).

In some embodiments, the immunomodulatory agent is a cytokine. In someembodiments, the immunomodulatory agent is a cytokine or is an agentthat induces increased expression of a cytokine in the tumormicroenvironment. Cytokines have important functions related to T cellexpansion, differentiation, survival, and homeostasis. Cytokines thatcan be administered to the subject receiving the binding molecules(e.g., BCMA-binding molecules), recombinant receptors, cells and/orcompositions provided herein include one or more of IL-2, IL-4, IL-7,IL-9, IL-15, IL-18, and IL-21. In some embodiments, the cytokineadministered is IL-7, IL-15, or IL-21, or a combination thereof. In someembodiments, administration of the cytokine to the subject that hassub-optimal response to the administration of the engineered cells,e.g., CAR-expressing cells improves efficacy and/or anti-tumor activityof the administered cells, e.g., CAR-expressing cells.

By “cytokine” is meant a generic term for proteins released by one cellpopulation that act on another cell as intercellular mediators. Examplesof such cytokines are lymphokines, monokines, and traditionalpolypeptide hormones. Included among the cytokines are growth hormonessuch as human growth hormone, N-methionyl human growth hormone, andbovine growth hormone; parathyroid hormone; thyroxine; insulin;proinsulin; relaxin; prorelaxin; glycoprotein hormones such as folliclestimulating hormone (FSH), thyroid stimulating hormone (TSH), andluteinizing hormone (LH); hepatic growth factor; fibroblast growthfactor; prolactin; placental lactogen; tumor necrosis factor-alpha and-beta; mullerian-inhibiting substance; mouse gonadotropin-associatedpeptide; inhibin; activin; vascular endothelial growth factor; integrin;thrombopoietin (TPO); nerve growth factors such as NGF-beta;platelet-growth factor; transforming growth factors (TGFs) such asTGF-alpha and TGF-beta; insulin-like growth factor-I and —II;erythropoietin (EPO); osteoinductive factors; interferons such asinterferon-alpha, beta, and -gamma; colony stimulating factors (CSFs)such as macrophage-CSF (M-CSF); granulocyte-macrophage-CSF (GM-CSF); andgranulocyte-CSF (G-CSF); interleukins (ILs) such as IL-1, IL-lalpha,IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12;IL-15, a tumor necrosis factor such as TNF-alpha or TNF-beta; and otherpolypeptide factors including LIF and kit ligand (KL). As used herein,the term cytokine includes proteins from natural sources or fromrecombinant cell culture, and biologically active equivalents of thenative sequence cytokines. For example, the immunomodulatory agent is acytokine and the cytokine is IL-4, TNF-α, GM-CSF or IL-2.

In some embodiments, the additional agent includes an interleukin-15(IL-15) polypeptide, an interleukin-15 receptor alpha (IL-15Ra)polypeptide, or combination thereof, e.g., hetIL-15 (AdmuneTherapeutics, LLC). hetIL-15 is a heterodimeric non-covalent complex ofIL-15 and IL-15Ra. hetIL-15 is described in, e.g., U.S. Pat. No.8,124,084, U.S. 2012/0177598, U.S. 2009/0082299, U.S. 2012/0141413, andU.S. 2011/0081311. In some embodiments, the immunomodulatory agent cancontain one or more cytokines. For example, the interleukin can includeleukocyte interleukin injection (Multikine), which is a combination ofnatural cytokines. In some embodiments, the immunomodulatory agent is aToll-like receptor (TLR) agonist, an adjuvant or a cytokine.

In some embodiments, the additional agent is an agent that amelioratesor neutralizes one or more toxicities or side effects associated withthe cell therapy. In some embodiments, the additional agent is selectedfrom among a steroid (e.g., corticosteroid), an inhibitor of TNFα, andan inhibitor of IL-6. An example of a TNFα inhibitor is an anti-TNFαantibody molecule such as, infliximab, adalimumab, certolizumab pegol,and golimumab. Another example of a TNFα inhibitor is a fusion proteinsuch as entanercept. Small molecule inhibitors of TNFα include, but arenot limited to, xanthine derivatives (e.g. pentoxifylline) andbupropion. An example of an IL-6 inhibitor is an anti-IL-6 antibodymolecule such as tocilizumab, sarilumab, elsilimomab, CNTO 328,ALD518/BMS-945429, CNTO 136, CPSI-2364, CDP6038, VX30, ARGX-109, FE301,and FM101. In some embodiments, the anti-IL-6 antibody molecule istocilizumab. In some embodiments, the additional agent is an IL-1Rinhibitor, such as anakinra.

In some embodiments, the additional agent is a modulator of adenosinelevels and/or an adenosine pathway component. Adenosine can function asan immunomodulatory agent in the body. For example, adenosine and someadenosine analogs that non-selectively activate adenosine receptorsubtypes decrease neutrophil production of inflammatory oxidativeproducts (Cronstein et al., Ann. N.Y. Acad. Sci. 451:291, 1985; Robertset al., Biochem. J., 227:669, 1985; Schrier et al., J. Immunol.137:3284, 1986; Cronstein et al., Clinical Immunol. Immunopath. 42:76,1987). In some cases, concentration of extracellular adenosine oradenosine analogs can increase in specific environments, e.g., tumormicroenvironment (TME). In some cases, adenosine or adenosine analogsignaling depends on hypoxia or factors involved in hypoxia or itsregulation, e.g., hypoxia inducible factor (HIF). In some embodiments,increase in adenosine signaling can increase in intracellular cAMP andcAMP-dependent protein kinase that results in inhibition ofproinflammatory cytokine production, and can lead to the synthesis ofimmunosuppressive molecules and development of Tregs (Sitkovsky et al.,Cancer Immunol Res (2014) 2(7):598-605). In some embodiments, theadditional agent can reduce or reverse immunosuppressive effects ofadenosine, adenosine analogs and/or adenosine signaling. In someembodiments, the additional agent can reduce or reverse hypoxia-drivenA2-adenosinergic T cell immunosuppression. In some embodiments, theadditional agent is selected from among antagonists of adenosinereceptors, extracellular adenosine-degrading agents, inhibitors ofadenosine generation by CD39/CD73 ectoenzymes, and inhibitors ofhypoxia-HIF-1α signaling. In some embodiments, the additional agent isan adenosine receptor antagonist or agonist.

Inhibition or reduction of extracellular adenosine or the adenosinereceptor by virtue of an inhibitor of extracellular adenosine (such asan agent that prevents the formation of, degrades, renders inactive,and/or decreases extracellular adenosine), and/or an adenosine receptorinhibitor (such as an adenosine receptor antagonist) can enhance immuneresponse, such as a macrophage, neutrophil, granulocyte, dendritic cell,T- and/or B cell-mediated response. In addition, inhibitors of the Gsprotein mediated cAMP dependent intracellular pathway and inhibitors ofthe adenosine receptor-triggered Gi protein mediated intracellularpathways, can also increase acute and chronic inflammation.

In some embodiments, the additional agent is an adenosine receptorantagonist or agonist, e.g., an antagonist or agonist of one or more ofthe adenosine receptors A2a, A2b, A1, and A3. A1 and A3 inhibit, and A2aand A2b stimulate, respectively, adenylate cyclase activity. Certainadenosine receptors, such as A2a, A2b, and A3, can suppress or reducethe immune response during inflammation. Thus, antagonizingimmunosuppressive adenosine receptors can augment, boost or enhanceimmune response, e.g., immune response from administered cells, e.g.,CAR-expressing T cells. In some embodiments, the additional agentinhibits the production of extracellular adenosine andadenosine-triggered signaling through adenosine receptors. For example,enhancement of an immune response, local tissue inflammation, andtargeted tissue destruction can be enhanced by inhibiting or reducingthe adenosine-producing local tissue hypoxia; by degrading (or renderinginactive) accumulated extracellular adenosine; by preventing ordecreasing expression of adenosine receptors on immune cells; and/or byinhibiting/antagonizing signaling by adenosine ligands through adenosinereceptors.

An antagonist is any substance that tends to nullify the action ofanother, as an agent that binds to a cell receptor without eliciting abiological response. In some embodiments, the antagonist is a chemicalcompound that is an antagonist for an adenosine receptor, such as theA2a, A2b, or A3 receptor. In some embodiments, the antagonist is apeptide, or a peptidomimetic, that binds the adenosine receptor but doesnot trigger a Gi protein dependent intracellular pathway. Exemplaryantagonists are described in U.S. Pat. Nos. 5,565,566; 5,545, 627,5,981,524; 5,861,405; 6,066,642; 6,326,390; 5,670,501; 6,117,998;6,232,297; 5,786,360; 5,424,297; 6,313,131, 5,504,090; and 6,322,771.

In some embodiments, the additional agent is an A2 receptor (A2R)antagonist, such as an A2a antagonist. Exemplary A2R antagonists includeKW6002 (istradefyline), SCH58261, caffeine, paraxanthine,3,7-dimethyl-1-propargylxanthine (DMPX), 8-(m-chlorostyryl) caffeine(CSC), MSX-2, MSX-3, MSX-4, CGS-15943, ZM-241385, SCH-442416,preladenant, vipadenant (BII014), V2006, ST-1535, SYN-115, PSB-1115,ZM241365, FSPTP, and an inhibitory nucleic acid targeting A2Rexpression, e.g., siRNA or shRNA, or any antibodies or antigen-bindingfragment thereof that targets an A2R. In some embodiments, theadditional agent is an A2R antagonist described in, e.g., Ohta et al.,Proc Natl Acad Sci USA (2006) 103:13132-13137; Jin et al., Cancer Res.(2010) 70(6):2245-2255; Leone et al., Computational and StructuralBiotechnology Journal (2015) 13:265-272; Beavis et al., Proc Natl AcadSci USA (2013) 110:14711-14716; and Pinna, A., Expert Opin InvestigDrugs (2009) 18:1619-1631; Sitkovsky et al., Cancer Immunol Res (2014)2(7):598-605; U.S. Pat. Nos. 8,080,554; 8,716,301; US 20140056922;WO2008/147482; U.S. Pat. No. 8,883,500; US 20140377240; WO02/055083;U.S. Pat. Nos. 7,141,575; 7,405,219; 8,883,500; 8,450,329 and8,987,279).

In some embodiments, the antagonist is an antisense molecule, inhibitorynucleic acid molecule (e.g., small inhibitory RNA (siRNA)) or catalyticnucleic acid molecule (e.g. a ribozyme) that specifically binds mRNAencoding an adenosine receptor. In some embodiments, the antisensemolecule, inhibitory nucleic acid molecule or catalytic nucleic acidmolecule binds nucleic acids encoding A2a, A2b, or A3. In someembodiments, an antisense molecule, inhibitory nucleic acid molecule orcatalytic nucleic acid targets biochemical pathways downstream of theadenosine receptor. For example, the antisense molecule or catalyticnucleic acid can inhibit an enzyme involved in the Gs protein- or Giprotein-dependent intracellular pathway. In some embodiments, theadditional agent includes dominant negative mutant form of an adenosinereceptor, such as A2a, A2b, or A3.

In some embodiments, the additional agent that inhibits extracellularadenosine includes agents that render extracellular adenosinenon-functional (or decrease such function), such as a substance thatmodifies the structure of adenosine to inhibit the ability of adenosineto signal through adenosine receptors. In some embodiments, theadditional agent is an extracellular adenosine-generating oradenosine-degrading enzyme, a modified form thereof or a modulatorthereof. For example, in some embodiments, the additional agent is anenzyme (e.g. adenosine deaminase) or another catalytic molecule thatselectively binds and destroys the adenosine, thereby abolishing orsignificantly decreasing the ability of endogenously formed adenosine tosignal through adenosine receptors and terminate inflammation.

In some embodiments, the additional agent is an adenosine deaminase(ADA) or a modified form thereof, e.g., recombinant ADA and/orpolyethylene glycol-modified ADA (ADA-PEG), which can inhibit localtissue accumulation of extracellular adenosine. ADA-PEG has been used intreatment of patients with ADA SCID (Hershfield (1995) Hum Mutat.5:107). In some embodiments, an agent that inhibits extracellularadenosine includes agents that prevent or decrease formation ofextracellular adenosine, and/or prevent or decrease the accumulation ofextracellular adenosine, thereby abolishing, or substantiallydecreasing, the immunosuppressive effects of adenosine. In someembodiments, the additional agent specifically inhibits enzymes andproteins that are involved in regulation of synthesis and/or secretionof pro-inflammatory molecules, including modulators of nucleartranscription factors. Suppression of adenosine receptor expression orexpression of the Gs protein- or Gi protein-dependent intracellularpathway, or the cAMP dependent intracellular pathway, can result in anincrease/enhancement of immune response.

In some embodiments, the additional agent can target ectoenzymes thatgenerate or produce extracellular adenosine. In some embodiments, theadditional agent targets CD39 and CD73 ectoenzymes, which function intandem to generate extracellular adenosine. CD39 (also calledectonucleoside triphosphate diphosphohydrolase) converts extracellularATP (or ADP) to 5′AMP. Subsequently, CD73 (also called 5′nucleotidase)converts 5′AMP to adenosine. The activity of CD39 is reversible by theactions of NDP kinase and adenylate kinase, whereas the activity of CD73is irreversible. CD39 and CD73 are expressed on tumor stromal cells,including endothelial cells and Tregs, and also on many cancer cells.For example, the expression of CD39 and CD73 on endothelial cells isincreased under the hypoxic conditions of the tumor microenvironment.Tumor hypoxia can result from inadequate blood supply and disorganizedtumor vasculature, impairing delivery of oxygen (Carroll and Ashcroft(2005), Expert. Rev. Mol. Med. 7(6):1-16). Hypoxia also inhibitsadenylate kinase (AK), which converts adenosine to AMP, leading to veryhigh extracellular adenosine concentration. Thus, adenosine is releasedat high concentrations in response to hypoxia, which is a condition thatfrequently occurs the tumor microenvironment (TME), in or around solidtumors. In some embodiments, the additional agent is one or more ofanti-CD39 antibody or antigen binding fragment thereof, anti-CD73antibody or antigen binding fragment thereof, e.g., MEDI9447 or TY/23,α-β-methylene-adenosine diphosphate (ADP), ARL 67156, POM-3, IPH52 (see,e.g., Allard et al. Clin Cancer Res (2013) 19(20):5626-5635; Hausler etal., Am J Transl Res (2014) 6(2):129-139; Zhang, B., Cancer Res. (2010)70(16):6407-6411).

In some embodiments, the additional agent is an inhibitor of hypoxiainducible factor 1 alpha (HIF-1α) signaling. Exemplary inhibitors ofHIF-1α include digoxin, acriflavine, sirtuin-7 and ganetespib.

In some embodiments, the additional agent includes a protein tyrosinephosphatase inhibitor, e.g., a protein tyrosine phosphatase inhibitordescribed herein. In some embodiments, the protein tyrosine phosphataseinhibitor is an SHP-1 inhibitor, e.g., an SHP-1 inhibitor describedherein, such as, e.g., sodium stibogluconate. In some embodiments, theprotein tyrosine phosphatase inhibitor is an SHP-2 inhibitor, e.g., anSHP-2 inhibitor described herein.

In some embodiments, the additional agent is a kinase inhibitor. Kinaseinhibitors, such as a CDK4 kinase inhibitor, a BTK kinase inhibitor, aMNK kinase inhibitor, or a DGK kinase inhibitor, can regulate theconstitutively active survival pathways that exist in tumor cells and/ormodulate the function of immune cells. In some embodiments, the kinaseinhibitor is a Bruton's tyrosine kinase (BTK) inhibitor, e.g.,ibrutinib. In some embodiments, the kinase inhibitor is aphosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. In someembodiments, the kinase inhibitor is a CDK4 inhibitor, e.g., a CDK4/6inhibitor. In some embodiments, the kinase inhibitor is an mTORinhibitor, such as, e.g., rapamycin, a rapamycin analog, OSI-027. ThemTOR inhibitor can be, e.g., an mTORC1 inhibitor and/or an mTORC2inhibitor, e.g., an mTORC1 inhibitor and/or mTORC2 inhibitor. In someembodiments, the kinase inhibitor is an MNK inhibitor, or a dualPI3K/mTOR inhibitor. In some embodiments, other exemplary kinaseinhibitors include the AKT inhibitor perifosine, the mTOR inhibitortemsirolimus, the Src kinase inhibitors dasatinib and fostamatinib, theJAK2 inhibitors pacritinib and ruxolitinib, the PKCβ inhibitorsenzastaurin and bryostatin, and the AAK inhibitor alisertib.

In some embodiments, the kinase inhibitor is a BTK inhibitor selectedfrom ibrutinib (PCI-32765); GDC-0834; RN-486; CGI-560; CGI-1764;HM-71224; CC-292; ONO-4059; CNX-774; and LFM-A13. In some embodiments,the BTK inhibitor does not reduce or inhibit the kinase activity ofinterleukin-2-inducible kinase (ITK), and is selected from GDC-0834;RN-486; CGI-560; CGI-1764; HM-71224; CC-292; ONO-4059; CNX-774; andLFM-A13.

In some embodiments, the kinase inhibitor is a BTK inhibitor, e.g.,ibrutinib(1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one;also known as PCI-32765). In some embodiments, the kinase inhibitor is aBTK inhibitor, e.g., ibrutinib (PCI-32765). In some embodiments, 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or more cycles of ibrutinib areadministered. In some embodiments, the BTK inhibitor is a BTK inhibitordescribed in International Application WO 2015/079417.

In some embodiments, the kinase inhibitor is a PI3K inhibitor. PI3K iscentral to the PI3K/Akt/mTOR pathway involved in cell cycle regulationand lymphoma survival. Exemplary PI3K inhibitor includes idelalisib(PI3Kδ inhibitor). In some embodiments, the additional agent isidelalisib and rituximab.

In some embodiments, the additional agent is an inhibitor of mammaliantarget of rapamycin (mTOR). In some embodiments, the kinase inhibitor isan mTOR inhibitor selected from temsirolimus; ridaforolimus (also knownas AP23573 and MK8669); everolimus (RAD001); rapamycin (AY22989);simapimod; AZD8055; PF04691502; SF1126; and XL765. In some embodiments,the additional agent is an inhibitor of mitogen-activated protein kinase(MAPK), such as vemurafenib, dabrafenib, and trametinib.

In some embodiments, the additional agent is an agent that regulatespro- or anti-apoptotic proteins. In some embodiments, the additionalagent includes a B-cell lymphoma 2 (BCL-2) inhibitor (e.g., venetoclax,also called ABT-199 or GDC-0199; or ABT-737). Venetoclax is a smallmolecule (4-(4-{[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide)that inhibits the anti-apoptotic protein, BCL-2. Other agents thatmodulate pro- or anti-apoptotic protein include BCL-2 inhibitor ABT-737,navitoclax (ABT-263); Mcl-1 siRNA or Mcl-1 inhibitor retinoidN-(4-hydroxyphenyl) retinamide (4-HPR) for maximal efficacy. In someembodiments, the additional agent provides a pro-apoptotic stimuli, suchas recombinant tumor necrosis factor-related apoptosis-inducing ligand(TRAIL), which can activate the apoptosis pathway by binding to TRAILdeath receptors DR-4 and DR-5 on tumor cell surface, or TRAIL-R2agonistic antibodies.

In some embodiments, the additional agent includes an indoleamine2,3-dioxygenase (IDO) inhibitor. IDO is an enzyme that catalyzes thedegradation of the amino acid, L-tryptophan, to kynurenine. Many cancersoverexpress IDO, e.g., prostatic, colorectal, pancreatic, cervical,gastric, ovarian, head, and lung cancer. Plasmacytoid dendritic cells(pDCs), macrophages, and dendritic cells (DCs) can express IDO. In someaspects, a decrease in L-tryptophan (e.g., catalyzed by IDO) results inan immunosuppressive milieu by inducing T-cell anergy and apoptosis.Thus, in some aspects, an IDO inhibitor can enhance the efficacy of thebinding molecules (e.g., BCMA-binding molecules), recombinant receptors,cells and/or compositions described herein, e.g., by decreasing thesuppression or death of the administered CAR-expressing cell. Exemplaryinhibitors of IDO include but are not limited to 1-methyl-tryptophan,indoximod, and INCB024360 (epacadostat).

In some embodiments, the additional agent includes a cytotoxic agent,e.g., CPX-351 (Celator Pharmaceuticals), cytarabine, daunorubicin,vosaroxin (Sunesis Pharmaceuticals), sapacitabine (CyclacelPharmaceuticals), idarubicin, or mitoxantrone. In some embodiments, theadditional agent includes a hypomethylating agent, e.g., a DNAmethyltransferase inhibitor, e.g., azacitidine or decitabine.

In another embodiment, the additional therapy is a transplantation,e.g., allogeneic stem cell transplant.

In some embodiments, the additional therapy is a lymphodepletingtherapy. In some embodiments, lymphodepletion is performed on a subject,e.g., prior to administering engineered cells, e.g., CAR-expressingcells. In some embodiments, the lymphodepletion comprises administeringone or more of melphalan, Cytoxan, cyclophosphamide, and fludarabine. Insome embodiments, a lymphodepleting chemotherapy is administered to thesubject prior to, concurrently with, or after administration (e.g.,infusion) of engineered cells, e.g., CAR-expressing cells. In anexample, the lymphodepleting chemotherapy is administered to the subjectprior to administration of engineered cells, e.g., CAR-expressing cells.

In some embodiments, the additional agent is an oncolytic virus. In someembodiments, oncolytic viruses are capable of selectively replicating inand triggering the death of or slowing the growth of a cancer cell. Insome cases, oncolytic viruses have no effect or a minimal effect onnon-cancer cells. An oncolytic virus includes but is not limited to anoncolytic adenovirus, oncolytic Herpes Simplex Viruses, oncolyticretrovirus, oncolytic parvovirus, oncolytic vaccinia virus, oncolyticSinbis virus, oncolytic influenza virus, or oncolytic RNA virus (e.g.,oncolytic reovirus, oncolytic Newcastle Disease Virus (NDV), oncolyticmeasles virus, or oncolytic vesicular stomatitis virus (VSV)).

Other exemplary combination therapy, treatment and/or agents includeanti-allergenic agents, anti-emetics, analgesics and adjunct therapies.In some embodiments, the additional agent includes cytoprotectiveagents, such as neuroprotectants, free-radical scavengers,cardioprotectors, anthracycline extravasation neutralizers andnutrients.

In some embodiments, an antibody used as an additional agent isconjugated or otherwise bound to a therapeutic agent, e.g., achemotherapeutic agent (e.g., Cytoxan, fludarabine, histone deacetylaseinhibitor, demethylating agent, peptide vaccine, anti-tumor antibiotic,tyrosine kinase inhibitor, alkylating agent, anti-microtubule oranti-mitotic agent), anti-allergic agent, anti-nausea agent (oranti-emetic), pain reliever, or cytoprotective agent described herein.In some embodiments, the additional agent is an antibody-drug conjugate.

In some embodiments, the additional agent can modulate, inhibit orstimulate particular factors at the DNA, RNA or protein levels, toenhance or boost the efficacy of the binding molecules (e.g.,BCMA-binding molecules), recombinant receptors, cells and/orcompositions provided herein. In some embodiments, the additional agentcan modulate the factors at the nucleic acid level, e.g., DNA or RNA,within the administered cells, e.g., cells engineered to expressrecombinant receptors, e.g., CAR. In some embodiments, an inhibitorynucleic acid, e.g., an inhibitory nucleic acid, e.g., a dsRNA, e.g., ansiRNA or shRNA, or a clustered regularly interspaced short palindromicrepeats (CRISPR), a transcription-activator like effector nuclease(TALEN), or a zinc finger endonuclease (ZFN), can be used to inhibitexpression of an inhibitory molecule in the engineered cell, e.g.,CAR-expressing cell. In some embodiments the inhibitor is an shRNA. Insome embodiments, the inhibitory molecule is inhibited within theengineered cell, e.g., CAR-expressing cell. In some embodiments, anucleic acid molecule that encodes a dsRNA molecule that inhibitsexpression of the molecule that modulates or regulates, e.g., inhibits,T-cell function is operably linked to a promoter, e.g., a HI- or aU6-derived promoter such that the dsRNA molecule that inhibitsexpression of the inhibitory molecule is expressed within the engineeredcell, e.g., CAR-expressing cell. See, e.g., Brummelkamp T R, et al.(2002) Science 296: 550-553; Miyagishi M, et al. (2002) Nat. Biotechnol.19: 497-500.

In some embodiments, the additional agent is capable of disrupting thegene encoding an inhibitory molecule, such as any immune checkpointinhibitors described herein. In some embodiments, disruption is bydeletion, e.g., deletion of an entire gene, exon, or region, and/orreplacement with an exogenous sequence, and/or by mutation, e.g.,frameshift or missense mutation, within the gene, typically within anexon of the gene. In some embodiments, the disruption results in apremature stop codon being incorporated into the gene, such that theinhibitory molecule is not expressed or is not expressed in a form thatis capable of being expressed on the cells surface and/or capable ofmediating cell signaling. The disruption is generally carried out at theDNA level. The disruption generally is permanent, irreversible, or nottransient.

In some aspects, the disruption is carried out by gene editing, such asusing a DNA binding protein or DNA-binding nucleic acid, whichspecifically binds to or hybridizes to the gene at a region targeted fordisruption. In some aspects, the protein or nucleic acid is coupled toor complexed with a nuclease, such as in a chimeric or fusion protein.For example, in some embodiments, the disruption is effected using afusion comprising a DNA-targeting protein and a nuclease, such as a ZincFinger Nuclease (ZFN) or TAL-effector nuclease (TALEN), or an RNA-guidednuclease such as a clustered regularly interspersed short palindromicnucleic acid (CRISPR)-Cas system, such as CRISPR-Cas9 system, specificfor the gene being disrupted. In some embodiments, methods of producingor generating genetically engineered cells, e.g., CAR-expressing cells,include introducing into a population of cells nucleic acid moleculesencoding a genetically engineered antigen receptor (e.g. CAR) andnucleic acid molecules encoding an agent targeting an inhibitorymolecule that is a gene editing nuclease, such as a fusion of aDNA-targeting protein and a nuclease such as a ZFN or a TALEN, or anRNA-guided nuclease such as of the CRISPR-Cas9 system, specific for aninhibitory molecule.

Any of the additional agents described herein can be prepared andadministered as combination therapy with the BCMA-binding molecule(e.g., antibody), immunoconjugate, recombinant receptor (e.g., chimericantigen receptor) and/or engineered cells expressing said molecules(e.g., recombinant receptor) described herein, such as in pharmaceuticalcompositions comprising one or more agents of the combination therapyand a pharmaceutically acceptable carrier, such as any described herein.In some embodiments, the BCMA-binding molecule (e.g., antibody),immunoconjugate, recombinant receptor (e.g., chimeric antigen receptor),engineered cells expressing said molecules (e.g., recombinant receptor),plurality of engineered cells expressing said molecules (e.g.,recombinant receptor) can be administered simultaneously, concurrentlyor sequentially, in any order with the additional agents, therapy ortreatment, wherein such administration provides therapeuticallyeffective levels each of the agents in the body of the subject. Theagents can be co-administered with the binding molecules (e.g.,BCMA-binding molecules), recombinant receptors, cells and/orcompositions described herein, for example, as part of the samepharmaceutical composition or using the same method of delivery. In someembodiments, the additional agent is incubated with the engineered cell,e.g., CAR-expressing cells, prior to administration of the cells.

In some examples, the one or more additional agents are administeredsubsequent to or prior to the administration of the binding molecules(e.g., BCMA-binding molecules), recombinant receptors, cells and/orcompositions described herein, separated by a selected time period. Insome examples, the time period is 1 day, 2 days, 3 days, 4 days, 5 days,6 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, or 3 months. Insome examples, the one or more additional agents are administeredmultiple times and/or the binding molecules (e.g., BCMA-bindingmolecules), recombinant receptors, cells and/or compositions describedherein, is administered multiple times. For example, in someembodiments, the additional agent is administered prior to the bindingmolecules (e.g., BCMA-binding molecules), recombinant receptors, cellsand/or compositions described herein, e.g., two weeks, 12 days, 10 days,8 days, one week, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day beforethe administration. For example, in some embodiments, the additionalagent is administered after the binding molecules (e.g., BCMA-bindingmolecules), recombinant receptors, cells and/or compositions describedherein, e.g., two weeks, 12 days, 10 days, 8 days, one week, 6 days, 5days, 4 days, 3 days, 2 days or 1 day after the administration.

The dose of the additional agent can be any therapeutically effectiveamount, e.g., any dose amount described herein, and the appropriatedosage of the additional agent may depend on the type of disease to betreated, the type, dose and/or frequency of the binding molecule,recombinant receptor, cell and/or composition administered, the severityand course of the disease, whether the binding molecule, recombinantreceptor, cell and/or composition is administered for preventive ortherapeutic purposes, previous therapy, the patient's clinical historyand response to the binding molecule, recombinant receptor, cell and/orcomposition, and the discretion of the attending physician. The bindingmolecule, recombinant receptor, cell and/or composition and/or theadditional agent and/or therapy can be administered to the patient atone time, repeated or administered over a series of treatments.

C. Diagnostic and Detection Methods

Also provided are methods involving use of the provided bindingmolecules, e.g., antibodies or antigen-binding fragments thereof, indetection of BCMA, for example, in diagnostic and/or prognostic methodsin association with a BCMA-expressing disease or condition. The methodsin some embodiments include incubating a biological sample with theantibody or antigen-binding fragment thereof and/or administering theantibody or antigen-binding fragment thereof to a subject. In certainembodiments, a biological sample includes a cell or tissue, such astumor or cancer tissue. In certain embodiments, the contacting is underconditions permissive for binding of the anti-BCMA antibody to BCMA, anddetecting whether a complex is formed between the anti-BCMA antibody andBCMA. Such a method may be an in vitro or in vivo method. In oneembodiment, an anti-BCMA antibody (e.g., antigen-binding fragment) isused to select subjects eligible for therapy with an anti-BCMA antibody(e.g., antigen-binding fragment) or recombinant receptor, e.g. whereBCMA is a biomarker for selection of patients.

In some embodiments, a sample, such as a cell, tissue sample, lysate,composition, or other sample derived therefrom is contacted with theanti-BCMA antibody (e.g., antigen-binding fragment) and binding orformation of a complex between the antibody and the sample (e.g., BCMAin the sample) is determined or detected. When binding in the testsample is demonstrated or detected as compared to a reference cell ofthe same tissue type, it may indicate the presence of an associateddisease or condition. In some embodiments, the sample is from humantissues.

Various methods known in the art for detecting specific antibody-antigenbinding can be used. Exemplary immunoassays include fluorescencepolarization immunoassay (FPIA), fluorescence immunoassay (FIA), enzymeimmunoassay (EIA), nephelometric inhibition immunoassay (NIA), enzymelinked immunosorbent assay (ELISA), and radioimmunoassay (RIA). Anindicator moiety, or label group, can be attached to the subjectantibodies and is selected so as to meet the needs of various uses ofthe method which are often dictated by the availability of assayequipment and compatible immunoassay procedures. Exemplary labelsinclude radionuclides (e.g. ¹²⁵I, ¹³¹I, ³⁵S, ³H, or ³²P), enzymes (e.g.,alkaline phosphatase, horseradish peroxidase, luciferase, orβ-galactosidase), fluorescent moieties or proteins (e.g., fluorescein,rhodamine, phycoerythrin, GFP, or BFP), or luminescent moieties (e.g.,Qdot nanoparticles supplied by the Quantum Dot Corporation, Palo Alto,Calif). General techniques to be used in performing the variousimmunoassays noted above are known to those of ordinary skill in theart.

For purposes of diagnosis, the antibodies (e.g., antigen-bindingfragments) can be labeled with a detectable moiety including but notlimited to radioisotopes, fluorescent labels, and variousenzyme-substrate labels know in the art. Methods of conjugating labelsto an antibody are known in the art.

In some embodiments, antibodies (e.g., antigen-binding fragments) neednot be labeled, and the presence thereof can be detected using a labeledantibody which binds to the antibodies.

The provided antibodies (e.g., antigen-binding fragments) in someembodiments can be employed in any known assay method, such ascompetitive binding assays, direct and indirect sandwich assays, andimmunoprecipitation assays. Zola, Monoclonal Antibodies: A Manual ofTechniques, pp. 147-158 (CRC Press, Inc. 1987).

The antibodies (e.g., antigen-binding fragments) and polypeptides canalso be used for in vivo diagnostic assays, such as in vivo imaging.Generally, the antibody is labeled with a radionuclide (such as ¹¹¹In,⁹⁹Tc, ¹⁴C, ¹³¹I, ¹²⁵I, or ³H) so that the cells or tissue of interestcan be localized in vivo following administration to a subject.

The antibody (e.g., antigen-binding fragment) may also be used asstaining reagent in pathology, e.g., using known techniques.

III. ARTICLES OF MANUFACTURE OR KITS

Also provided are articles of manufacture or kit containing the providedbinding molecules (e.g., antibodies), recombinant receptors (e.g.,CARs), genetically engineered cells, and/or compositions comprising thesame. The articles of manufacture may include a container and a label orpackage insert on or associated with the container. Suitable containersinclude, for example, bottles, vials, syringes, test tubes, IV solutionbags, etc. The containers may be formed from a variety of materials suchas glass or plastic. In some embodiments, the container has a sterileaccess port. Exemplary containers include an intravenous solution bags,vials, including those with stoppers pierceable by a needle forinjection. The article of manufacture or kit may further include apackage insert indicating that the compositions can be used to treat aparticular condition such as a condition described herein (e.g.,multiple myeloma). Alternatively, or additionally, the article ofmanufacture or kit may further include another or the same containercomprising a pharmaceutically-acceptable buffer. It may further includeother materials such as other buffers, diluents, filters, needles,and/or syringes.

The label or package insert may indicate that the composition is usedfor treating the BCMA-expressing or BCMA-associated disease, disorder orcondition in an individual. The label or a package insert, which is onor associated with the container, may indicate directions forreconstitution and/or use of the formulation. The label or packageinsert may further indicate that the formulation is useful or intendedfor subcutaneous, intravenous, or other modes of administration fortreating or preventing a BCMA-expressing or BCMA-associated disease,disorder or condition in an individual.

The container in some embodiments holds a composition which is by itselfor combined with another composition effective for treating, preventingand/or diagnosing the condition. The article of manufacture or kit mayinclude (a) a first container with a composition contained therein(i.e., first medicament), wherein the composition includes the antibody(e.g., anti-BCMA antibody) or antigen-binding fragment thereof orrecombinant receptor (e.g., CAR); and (b) a second container with acomposition contained therein (i.e., second medicament), wherein thecomposition includes a further agent, such as a cytotoxic or otherwisetherapeutic agent, and which article or kit further comprisesinstructions on the label or package insert for treating the subjectwith the second medicament, in an effective amount.

IV. DEFINITIONS

As used herein, reference to a “corresponding form” of an antibody meansthat when comparing a property or activity of two antibodies, theproperty is compared using the same form of the antibody. For example,if it is stated that an antibody has greater activity compared to theactivity of the corresponding form of a first antibody, that means thata particular form, such as an scFv of that antibody, has greateractivity compared to the scFv form of the first antibody.

“Effector functions” refer to those biological activities attributableto the Fc region of an antibody, which vary with the antibody isotype.Examples of antibody effector functions include: Clq binding andcomplement dependent cytotoxicity (CDC); Fc receptor binding;antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; downregulation of cell surface receptors (e.g. B cell receptor); and B cellactivation.

The term “Fc region” herein is used to define a C-terminal region of animmunoglobulin heavy chain that contains at least a portion of theconstant region. The term includes native sequence Fc regions andvariant Fc regions. In one embodiment, a human IgG heavy chain Fc regionextends from Cys226, or from Pro230, to the carboxyl-terminus of theheavy chain. However, the C-terminal lysine (Lys447) of the Fc regionmay or may not be present. Unless otherwise specified herein, numberingof amino acid residues in the Fc region or constant region is accordingto the EU numbering system, also called the EU index, as described inKabat et al., Sequences of Proteins of Immunological Interest, 5th Ed.Public Health Service, National Institutes of Health, Bethesda, M D,1991.

The terms “full length antibody,” “intact antibody,” and “wholeantibody” are used herein interchangeably to refer to an antibody havinga structure substantially similar to a native antibody structure orhaving heavy chains that contain an Fc region as defined herein.

An “isolated” antibody is one which has been separated from a componentof its natural environment. In some embodiments, an antibody is purifiedto greater than 95% or 99% purity as determined by, for example,electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillaryelectrophoresis) or chromatographic (e.g., ion exchange or reverse phaseHPLC). For review of methods for assessment of antibody purity, see,e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

An “isolated” nucleic acid refers to a nucleic acid molecule that hasbeen separated from a component of its natural environment. An isolatednucleic acid includes a nucleic acid molecule contained in cells thatordinarily contain the nucleic acid molecule, but the nucleic acidmolecule is present extrachromosomally or at a chromosomal location thatis different from its natural chromosomal location.

“Isolated nucleic acid encoding an anti-BCMA antibody” refers to one ormore nucleic acid molecules encoding antibody heavy and light chains (orfragments thereof), including such nucleic acid molecule(s) in a singlevector or separate vectors, and such nucleic acid molecule(s) present atone or more locations in a host cell.

The terms “host cell,” “host cell line,” and “host cell culture” areused interchangeably and refer to cells into which exogenous nucleicacid has been introduced, including the progeny of such cells. Hostcells include “transformants” and “transformed cells,” which include theprimary transformed cell and progeny derived therefrom without regard tothe number of passages. Progeny may not be completely identical innucleic acid content to a parent cell, but may contain mutations. Mutantprogeny that have the same function or biological activity as screenedor selected for in the originally transformed cell are included herein.

As used herein, “percent (%) amino acid sequence identity” and “percentidentity” and “sequence identity” when used with respect to an aminoacid sequence (reference polypeptide sequence) is defined as thepercentage of amino acid residues in a candidate sequence (e.g., thesubject antibody or fragment) that are identical with the amino acidresidues in the reference polypeptide sequence, after aligning thesequences and introducing gaps, if necessary, to achieve the maximumpercent sequence identity, and not considering any conservativesubstitutions as part of the sequence identity. Alignment for purposesof determining percent amino acid sequence identity can be achieved invarious ways that are within the skill in the art, for instance, usingpublicly available computer software such as BLAST, BLAST-2, ALIGN orMegalign (DNASTAR) software. Those skilled in the art can determineappropriate parameters for aligning sequences, including any algorithmsneeded to achieve maximal alignment over the full length of thesequences being compared.

An amino acid substitution may include replacement of one amino acid ina polypeptide with another amino acid. Amino acid substitutions may beintroduced into a binding molecule, e.g., antibody, of interest and theproducts screened for a desired activity, e.g., retained/improvedantigen binding, decreased immunogenicity, or improved ADCC or CDC.

Amino acids generally can be grouped according to the following commonside-chain properties:

-   -   (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile;    -   (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln;    -   (3) acidic: Asp, Glu;    -   (4) basic: His, Lys, Arg;    -   (5) residues that influence chain orientation: Gly, Pro;    -   (6) aromatic: Trp, Tyr, Phe.

Non-conservative amino acid substitutions will involve exchanging amember of one of these classes for another class.

The term “vector,” as used herein, refers to a nucleic acid moleculecapable of propagating another nucleic acid to which it is linked. Theterm includes the vector as a self-replicating nucleic acid structure aswell as the vector incorporated into the genome of a host cell intowhich it has been introduced. Certain vectors are capable of directingthe expression of nucleic acids to which they are operatively linked.Such vectors are referred to herein as “expression vectors.”

The term “package insert” is used to refer to instructions customarilyincluded in commercial packages of therapeutic products, that containinformation about the indications, usage, dosage, administration,combination therapy, contraindications and/or warnings concerning theuse of such therapeutic products.

As used herein, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. For example,“a” or “an” means “at least one” or “one or more.” It is understood thataspects, embodiments, and variations described herein include“comprising,” “consisting,” and/or “consisting essentially of” aspects,embodiments and variations.

Throughout this disclosure, various aspects of the claimed subjectmatter are presented in a range format. It should be understood that thedescription in range format is merely for convenience and brevity andshould not be construed as an inflexible limitation on the scope of theclaimed subject matter. Accordingly, the description of a range shouldbe considered to have specifically disclosed all the possible sub-rangesas well as individual numerical values within that range. For example,where a range of values is provided, it is understood that eachintervening value, between the upper and lower limit of that range andany other stated or intervening value in that stated range isencompassed within the claimed subject matter. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges, and are also encompassed within the claimed subjectmatter, subject to any specifically excluded limit in the stated range.Where the stated range includes one or both of the limits, rangesexcluding either or both of those included limits are also included inthe claimed subject matter. This applies regardless of the breadth ofthe range.

The term “about” as used herein refers to the usual error range for therespective value readily known to the skilled person in this technicalfield. Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

As used herein, a “composition” refers to any mixture of two or moreproducts, substances, or compounds, including cells. It may be asolution, a suspension, liquid, powder, a paste, aqueous, non-aqueous orany combination thereof.

As used herein, a statement that a cell or population of cells is“positive” for a particular marker refers to the detectable presence onor in the cell of a particular marker, typically a surface marker. Whenreferring to a surface marker, the term refers to the presence ofsurface expression as detected by flow cytometry, for example, bystaining with an antibody that specifically binds to the marker anddetecting said antibody, wherein the staining is detectable by flowcytometry at a level substantially above the staining detected carryingout the same procedure with an isotype-matched control under otherwiseidentical conditions and/or at a level substantially similar to that forcell known to be positive for the marker, and/or at a levelsubstantially higher than that for a cell known to be negative for themarker.

As used herein, a statement that a cell or population of cells is“negative” for a particular marker refers to the absence of substantialdetectable presence on or in the cell of a particular marker, typicallya surface marker. When referring to a surface marker, the term refers tothe absence of surface expression as detected by flow cytometry, forexample, by staining with an antibody that specifically binds to themarker and detecting said antibody, wherein the staining is not detectedby flow cytometry at a level substantially above the staining detectedcarrying out the same procedure with an isotype-matched control underotherwise identical conditions, and/or at a level substantially lowerthan that for cell known to be positive for the marker, and/or at alevel substantially similar as compared to that for a cell known to benegative for the marker.

Unless defined otherwise, all terms of art, notations and othertechnical and scientific terms or terminology used herein are intendedto have the same meaning as is commonly understood by one of ordinaryskill in the art to which the claimed subject matter pertains. In somecases, terms with commonly understood meanings are defined herein forclarity and/or for ready reference, and the inclusion of suchdefinitions herein should not necessarily be construed to represent asubstantial difference over what is generally understood in the art.

IV. EXEMPLARY EMBODIMENTS

Among the embodiments provided herein are:

1. An antibody or antigen-binding fragment thereof, wherein saidantibody or antigen-binding fragment comprises a heavy chain variable(V_(H)) region comprising:

-   -   a heavy chain complementarity determining region 3 (CDR-H3)        comprising the amino acid sequence selected from any one of SEQ        ID NOs:7-11, 149-157, 279-287 and 376-378; or    -   a CDR-H3 contained within the heavy chain variable (V_(H))        region amino acid sequence selected from any one of SEQ ID        NOs:110-115, 247-256, 518-531 and 533.

2. An antibody or antigen-binding fragment thereof, wherein saidantibody or antigen-binding fragment comprises a V_(H) region having atleast 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequenceidentity to the V_(H) region amino acid sequence selected from any oneof SEQ ID NOs:110-115, 247-256, 518-531 and 533.

3. The antibody or antigen-binding fragment of embodiment 2, wherein theV_(H) region comprises a CDR-H3 comprising the amino acid sequenceX₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃X₁₄ (SEQ ID NO:355), wherein Xi is A, D,E, G, L, V or W; X₂ is A, D, G, L, P, Q or S; X₃ is A, D, G, L or Y; X₄is D, G, P, R, S, V, Y or null; X₅ is D, I, P, S, T, Y or null; X₆ is A,G, I, S, T, V, Y or null; X₇ is A, D, E, F, L, P, S, Y or null; X₈ is P,Q, T, Y or null; X₉ is D, G, R, Y or null; X₁₀ is A, F, Y or null; X₁₁is D, F or null; X₁₂ is F or null; X₁₃ is D, T or Y; and X₁₄ is I, L, N,V or Y.

4. The antibody or antigen-binding fragment of embodiment 2 orembodiment 3, wherein the V_(H) region comprises:

-   -   a CDR-H3 comprising the amino acid sequence selected from any        one of SEQ ID NOs:7-11, 149-157, 279-287 and 376-378; or    -   a CDR-H3 contained within the V_(H) region amino acid sequence        selected from any one of SEQ ID NOs:110-115, 247-256, 518-531        and 533.

5. The antibody or antigen-binding fragment of any one of embodiments1-4, wherein the V_(H) region comprises:

-   -   a heavy chain complementarity determining region 1 (CDR-H1)        comprising the amino acid sequence X₁X₂X₃MX₄ (SEQ ID NO:353) Xi        is D or S; X₂ is Y or S; X₃ is A, G, W, or Y;    -   and X₄ is H, Q, or S; and/or a heavy chain complementarity        determining region 2 (CDR-H2) comprising the amino acid sequence        X₁₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁YX₁₂X₁₃X₁₄X₁₅X₁₆X₁₇ (SEQ ID NO:354),        wherein Xi is F, G, H, V, W or Y; X₂ is N, R, S or V; X₃ is P,        Q, S, V, W or Y; X₄ is K or null; X₅ is A or null; X₆ is D, G,        N, S, or Y; X₇ is G or S; X₈ is G or S; X₉ is E, G, N, T or S;        X₁₀ is I, K, or T; X₁₁ is E, G, N or Y; X₁₂ is A or V; X₁₃ is A,        D or Q; X₁₄ is K or S; X₁₅ is F or V; X₁₆ is K or Q; and X₁₇ is        E or G.

6. The antibody or antigen-binding fragment of any one of embodiments1-5, wherein the V_(H) region comprises:

-   -   a heavy chain complementarity determining region 1 (CDR-H1)        comprising the amino acid sequence selected from any one of SEQ        ID NOs:1-3 and 140-144; and/or    -   a heavy chain complementarity determining region 2 (CDR-H2)        comprising the amino acid sequence selected from any one of SEQ        ID NOs:4-6, 145-148 and 372-374.

7. The antibody or antigen-binding fragment of any one of embodiments1-6, wherein the V_(H) region comprises:

-   -   a CDR-H1 contained within the V_(H) region amino acid sequence        selected from any one of SEQ ID NOs:110-115, 247-256, 518-531        and 533; and/or    -   a CDR-H2 contained within the V_(H) region amino acid sequence        selected from any one of SEQ ID NOs:110-115, 247-256, 518-531        and 533.

8. The antibody or antigen-binding fragment thereof of embodiment 7,wherein:

-   -   the CDR-H1 comprises the amino acid sequence selected from any        one of SEQ ID NOs: 1-3, 141, 143 and 144 or a CDR-H1 contained        within the V_(H) region amino acid sequence selected from any        one of SEQ ID NOs:110-113, 115, 248, 252-256 and 518-522;    -   the CDR-H2 comprises the amino acid sequence selected from any        one of SEQ ID NOs: 4-6, 145, 147, 148 and 372 or a CDR-H2        contained within the V_(H) region amino acid sequence selected        from any one of SEQ ID NOs:110-113, 115, 248, 252-256 and        518-522; and/or    -   the CDR-H3 comprises the amino acid sequence selected from any        one of SEQ ID NOs: 7-10, 149, 153-157 and 376 or a CDR-H3        contained within the V_(H) region amino acid sequence selected        from any one of SEQ ID NOs:110-113, 115, 248, 252-256 and        518-522.

9. The antibody or antigen-binding fragment thereof of embodiment 7 orembodiment 8, wherein:

-   -   the CDR-H1 comprises the amino acid sequence of SEQ ID NO:1 or a        CDR-H1 contained within the V_(H) region amino acid sequence        selected from any one of SEQ ID NOs: 115 and 256;    -   the CDR-H2 comprises the amino acid sequence of SEQ ID NO:5 or a        CDR-H2 contained within the V_(H) region amino acid sequence        selected from any one of SEQ ID NOs: 115 and 256; and/or    -   the CDR-H3 comprises the amino acid sequence selected from any        one of SEQ ID NOs: 10 and 157 or a CDR-H3 contained within the        V_(H) region amino acid sequence selected from any one of SEQ ID        NOs: 115 and 256.

10. An antibody or antigen-binding fragment thereof, comprising a heavychain variable (V_(H)) region comprising a heavy chain complementaritydetermining region 1 (CDR-H1), CDR-H2, and CDR-H3, wherein:

-   -   the CDR-H1 comprises the amino acid sequence selected from any        one of SEQ ID NOs:1-3 and 140-144 or a CDR-H1 contained within        the V_(H) region amino acid sequence selected from any one of        SEQ ID NOs:110-115, 247-256, 518-531 and 533;    -   the CDR-H2 comprises the amino acid sequence selected from any        one of SEQ ID NOs:4-6, 145-148 and 372-374 or a CDR-H2 contained        within the V_(H) region amino acid sequence selected from any        one of SEQ ID NOs:110-115, 247-256, 518-531 and 533; and/or    -   the CDR-H3 comprises the amino acid sequence selected from any        one of SEQ ID NOs:7-11, 149-157, 279-287 and 376-378 or a CDR-H3        contained within the V_(H) region amino acid sequence selected        from any one of SEQ ID NOs:110-115, 247-256, 518-531 and 533.

11. The antibody or antigen-binding fragment thereof of embodiment 10,wherein:

-   -   the CDR-H1 comprises the amino acid sequence selected from any        one of SEQ ID NOs: 1-3, 141, 143 and 144 or a CDR-H1 contained        within the V_(H) region amino acid sequence selected from any        one of SEQ ID NOs:110-113, 115, 248, 252-256 and 518-522;    -   the CDR-H2 comprises the amino acid sequence selected from any        one of SEQ ID NOs: 4-6, 145, 147, 148 and 372 or a CDR-H2        contained within the V_(H) region amino acid sequence selected        from any one of SEQ ID NOs:110-113, 115, 248, 252-256 and        518-522; and/or    -   the CDR-H3 comprises the amino acid sequence selected from any        one of SEQ ID NOs: 7-10, 149, 153-157 and 376 or a CDR-H3        contained within the V_(H) region amino acid sequence selected        from any one of SEQ ID NOs:110-113, 115, 248, 252-256 and        518-522.

12. The antibody or antigen-binding fragment thereof of embodiment 10 orembodiment 11, wherein:

-   -   the CDR-H1 comprises the amino acid sequence of SEQ ID NO:1 or a        CDR-H1 contained within the V_(H) region amino acid sequence        selected from any one of SEQ ID NOs: 115 and 256;    -   the CDR-H2 comprises the amino acid sequence of SEQ ID NO:5 or a        CDR-H2 contained within the V_(H) region amino acid sequence        selected from any one of SEQ ID NOs: 115 and 256; and/or    -   the CDR-H3 comprises the amino acid sequence selected from any        one of SEQ ID NOs: 10 and 157 or a CDR-H3 contained within the        V_(H) region amino acid sequence selected from any one of SEQ ID        NOs: 115 and 256.

13. The antibody or antigen-binding fragment of any one of embodiments1-10, comprising a V_(H) region comprising a CDR-H1, CDR-H2, and CDR-H3,selected from:

-   -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:1, 4, and 7, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:2, 5, and 8, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:2, 5, and 9, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:2, 5, and 10, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:3, 6, and 11, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:140, 145, and 149, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:141, 145, and 149, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:141, 145, and 150, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:142, 146, and 151, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:2, 5, and 152, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:143, 147, and 153, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:144, 148, and 154, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:3, 6, and 155, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:2, 5, and 156, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:2, 5, and 157, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:2, 6, and 376, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:3, 372, and 376, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:3, 6, and 376, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:3, 6, and 377, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:2, 373, and 152, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:2, 5, and 378, respectively; or a CDR-H1, CDR-H2,        and CDR-H3 comprising the amino acid sequence of SEQ ID NOs:2,        374, and 9, respectively.

14. The antibody or antigen-binding fragment of embodiment 13, whereinthe CDR-H1, CDR-H2, and CDR-H3, are selected from:

-   -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:1, 4, and 7, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:2, 5, and 8, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:2, 5, and 9, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:2, 5, and 10, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:141, 145, and 149, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:143, 147, and 153, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:144, 148, and 154, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:3, 6, and 155, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:2, 5, and 156, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:2, 5, and 157, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:2, 6, and 376, respectively;    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs:3, 372, and 376, respectively; or    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of and SEQ ID NOs:3, 6, and 376, respectively;

15. The antibody or antigen-binding fragment of embodiment 13, whereinthe CDR-H1, CDR-H2, and CDR-H3, are selected from:

-   -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of SEQ ID NOs: 2, 5, and 10, respectively; or    -   a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequence        of and SEQ ID NOs: 2, 5, and 157, respectively;    -   16. An antibody or antigen-binding fragment thereof, wherein        said antibody or antigen-binding fragment comprises a V_(H)        region comprising a CDR-H1, a CDR-H2, and a CDR-H3,        respectively, comprising the amino acid sequence of a CDR-H1, a        CDR-H2, and a CDR-H3 contained within the V_(H) region amino        acid sequence selected from any one of SEQ ID NOs:110-115,        247-256, 518-531 and 533.

17. The antibody or antigen-binding fragment thereof of embodiment 16,wherein the CDR-H1, the CDR-H2, and the CDR-H3, respectively, comprisethe amino acid sequence of a CDR-H1, a CDR-H2, and a CDR-H3 containedwithin the V_(H) region amino acid sequence selected from any one of SEQID NOs: 110-113, 115, 248, 252-256 and 518-522.

18. The antibody or antigen-binding fragment thereof of embodiment 16 orembodiment 17, wherein the CDR-H1, the CDR-H2, and the CDR-H3,respectively, comprise the amino acid sequence of a CDR-H1, a CDR-H2,and a CDR-H3 contained within the V_(H) region amino acid sequenceselected from any one of SEQ ID NOs: 115 and 256.

19. The antibody or antigen-binding fragment of any one of embodiments1-16, wherein the V_(H) region comprises a framework region 1 (FR1), aFR2, a FR3, and/or a FR4 having at least 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity, respectively, to a FR1, FR2,FR3, and/or FR4 contained within the V_(H) region amino acid sequenceselected from any one of SEQ ID NOs:110-115, 247-256, 518-531 and 533.

20. The antibody or antigen-binding fragment of any one of embodiments1-19, wherein the V_(H) region comprises a FR1, a FR2, a FR3, and/or aFR4, selected from:

-   -   a FR1 comprising the amino acid sequence selected from any one        of SEQ ID NOs:59-63, 195-203 and 434-439;    -   the FR2 comprising the amino acid sequence selected from any one        of SEQ ID NOs:64-66 and 204-209;    -   a FR3 comprising the amino acid sequence selected from any one        of SEQ ID NOs:67-69, 210-216, 441 and 443; and/or    -   a FR4 comprising the amino acid sequence selected from any one        of SEQ ID NOs:70-71, 217-220, 444 and 445.

21. The antibody or antigen-binding fragment of any one of embodiments1-16, wherein the V_(H) region comprises the amino acid sequenceselected from any one of SEQ ID NOs:110-115, 247-256, 518-531 and 533.

22. The antibody or antigen-binding fragment thereof of embodiment 21,wherein the V_(H) region comprises the amino acid sequence selected fromany one of SEQ ID NOs: 110-113, 115, 248, 252-256 and 518-522.

23. The antibody or antigen-binding fragment thereof of embodiment 21 orembodiment 22, wherein the V_(H) region comprises the amino acidsequence selected from any one of SEQ ID NOs: 115 and 256.

24. The antibody or antigen-binding fragment of any one of embodiments1-21, wherein the antibody or antigen-binding fragment does not comprisea light chain variable (V_(L)) region, does not comprise a light chaincomplementarity determining region (CDR-L1), CDR-L2, and/or CDR-L3,and/or is a single-domain antibody (sdAb) comprising only the V_(H)region.

25. The antibody or antigen-binding fragment of any one of embodiments1-24, wherein the antibody or antigen-binding fragment is an sdAbcomprising only the V_(H) region.

26. The antibody or antigen-binding fragment of any one of embodiments1-21, wherein the antibody or antigen-binding fragment further comprisesa V_(L) region.

27. The antibody or antigen-binding fragment of embodiment 26, whereinthe V_(L) region has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, or 99% sequence identity to the V_(L) region amino acid sequenceselected from any one of SEQ ID NOs:116-127, 257-267, 534-550 and552-557.

28. The antibody or antigen-binding fragment of embodiment 26 orembodiment 27, wherein the V_(L) region comprises a light chaincomplementarity determining region 3 (CDR-L3) comprising the amino acidsequence X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂, (SEQ ID NO:358), wherein Xi is A,C, G, H, I, Q or S; X₂ is A, Q, S or V; X₃ is 5, W or Y; X₄ is D, F, G,H or Y; X₅ is D, G, M, R, S or T; X₆ is A, G, H, L, R, S, T or Y; X₇ isL, P, R, S or null; X₈ is D, G, N, R, S, T or null; X₉ is A, G, H, L, Por null; X₁₀ is F, S or null; X₁₁ is L, P, W or Y; and X₁₂ is S, T or V.

29. The antibody of antigen-binding fragment of any one of embodiments26-28, wherein the V_(L) region comprises a light chain complementaritydetermining region 3 (CDR-L3) comprising the amino acid sequenceselected from any one of SEQ ID NOs:47-58, 184-194, 415-427 and 429-433,or a CDR-L3 contained within the V_(L) region amino acid sequenceselected from any one of SEQ ID NOs:116-127, 257-267, 534-550 and552-557.

30. The antibody or antigen-binding fragment of any one of embodiments26-29, wherein the V_(L) region comprises:

a light chain complementarity determining region 1 (CDR-L1) comprisingthe amino acid sequence X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁X₁₂X₁₃X₁₄X₁₅X₁₆X₁₇ (SEQID NO:356), wherein Xi is G, K, R, S or T; X₂ is A, G or S; X₃ is G, N,S or T; X₄ is G, K, N, Q, R or S; X₅ is S or null; X₆ is D, N, V ornull; X₇ is L, V or null; X₈ is H, S, Y or null; X₉ is S, T or null; X₁₀is S or null; X₁₁ is D, G, I, N, S or null; X₁₂ is D, E, G, K, I, N ornull; X₁₃ is F, G, K, N, R, S, Y or null; X₁₄ is D, K, N, T or null; X₁₅is A, D, G, L, N, S, T or Y; X₁₆ is L or V; X₁₇ is A, H, N, Q or S;and/or a light chain complementarity determining region 2 (CDR-L2)comprising the amino acid sequence X₁X₂X₃X₄X₅X₆X₇ (SEQ ID NO:357),wherein Xi is A, D, E, N, S, V or W; X₂ is A, D, N, S or V; X₃ is A, D,H, I, N or S; X₄ is D, K, N, Q, R or T; X₅ is L, R or V; X₆ is A, E, Por Q; and X₇ is A, D, S or T.

31. The antibody or antigen-binding fragment of any one of embodiments26-30, wherein the V_(L) region comprises:

-   -   a light chain complementarity determining region 1 (CDR-L1)        comprising the amino acid sequence selected from any one of SEQ        ID NOs:26-36, 174-178, 380-392 and 394-398; and/or    -   a light chain complementarity determining region 2 (CDR-L2)        comprising the amino acid sequence selected from any one of SEQ        ID NOs:37-46, 179-183, 399-409 and 411-414.

32. The antibody or antigen-binding fragment of any one of embodiments26-31, wherein the V_(L) region comprises:

-   -   a CDR-L1 contained within the V_(L) region amino acid sequence        selected from any one of SEQ ID NOs:116-127, 257-267, 534-550        and 552-557; and/or    -   a CDR-L2 contained within the V_(L) region amino acid sequence        selected from any one of SEQ ID NOs:116-127, 257-267, 534-550        and 552-557.

33. The antibody or antigen-binding fragment of any one of embodiments26-32, wherein the V_(L) region comprises:

-   -   a CDR-L1 comprising the amino acid sequence selected from any        one of SEQ ID NOs:26-36, 174-178, 380-392 and 394-398;    -   a CDR-L2 comprising the amino acid sequence selected from any        one of SEQ ID NOs:37-46, 179-183, 399-409 and 411-414; and/or    -   a CDR-L3 comprising the amino acid sequence selected from any        one of SEQ ID NOs:47-58, 184-194, 415-427 and 429-433.

34. The antibody or antigen-binding fragment of embodiment 33, whereinthe V_(L) region comprises:

-   -   a CDR-L1 comprising the amino acid sequence selected from any        one of SEQ ID NOs: 26-28, 30, 31, 33, 34, 174, 176-178 and        380-382;    -   a CDR-L2 comprising the amino acid sequence selected from any        one of SEQ ID NOs: 37-39, 41, 43, 44, 179, 181-183 and 399-401;        and/or    -   a CDR-L3 comprising the amino acid sequence selected from any        one of SEQ ID NOs: 47-49, 51, 52, 55, 56, 185, 189-194, 415-418        and 421.

35. The antibody or antigen-binding fragment of embodiment 33 orembodiment 34, wherein the V_(L) region comprises:

-   -   a CDR-L1 comprising the amino acid sequence selected from any        one of SEQ ID NOs: 33 and 178;    -   a CDR-L2 comprising the amino acid sequence selected from any        one of SEQ ID NOs: 43 and 183; and/or    -   a CDR-L3 comprising the amino acid sequence selected from any        one of SEQ ID NOs: 194 and 421.

36. The antibody or antigen-binding fragment of any one of embodiments26-33, wherein the V_(L) region comprises a CDR-L1, CDR-L2, and CDR-L3selected from:

-   -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:26, 37, and 47, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:27, 38, and 48, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:28, 39, and 49, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:29, 40, and 50, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:30, 39, and 51, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:31, 41, and 52, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:32, 42, and 53, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:30, 39, and 54, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:33, 43, and 55, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:34, 44, and 56, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:35, 45, and 57, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:36, 46, and 58, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:174, 179, and 184, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:174, 179, and 185, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:174, 179, and 186, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:174, 179, and 187, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:175, 180, and 188, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:174, 179, and 189, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:176, 181, and 190, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:177, 182, and 191, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:174, 179, and 192, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:178, 183, and 193, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:178, 183, and 194, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:30, 399, and 415, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:380, 400, and 416, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:33, 43, and 421, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:381, 401, and 417, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:382, 402, and 418, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:383, 403, and 419, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:384, 39, and 54, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:385, 180, and 58, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:175, 180, and 188, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:386, 404, and 420, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:387, 405, and 422, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:388, 406, and 423, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:388, 407, and 424, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:389, 408, and 425, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:390, 183, and 193, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:391, 409, and 426, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:392, 40, and 427, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:394, 39, and 429, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:395, 411, and 430, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:396, 412, and 431, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:396, 412, and 58, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:397, 413, and 432, respectively; or a CDR-L1,        CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID        NOs:398, 414, and 433, respectively.

37. The antibody or antigen-binding fragment of embodiment 36, whereinthe CDR-L1, CDR-L2, and CDR-L3 are selected from:

-   -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:26, 37, and 47, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:27, 38, and 48, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:28, 39, and 49, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:29, 40, and 50, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:30, 39, and 51, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:31, 41, and 52, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:32, 42, and 53, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:30, 39, and 54, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:33, 43, and 55, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:34, 44, and 56, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:35, 45, and 57, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:36, 46, and 58, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:174, 179, and 184, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:174, 179, and 185, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:174, 179, and 186, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:174, 179, and 187, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:175, 180, and 188, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:174, 179, and 189, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:176, 181, and 190, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:177, 182, and 191, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:174, 179, and 192, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:178, 183, and 193, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:178, 183, and 194, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:30, 399, and 415, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:380, 400, and 416, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:33, 43, and 421, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:381, 401, and 417, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:382, 402, and 418, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:383, 403, and 419, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:384, 39, and 54, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:385, 180, and 58, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:175, 180, and 188, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:386, 404, and 420, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:387, 405, and 422, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:388, 406, and 423, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:388, 407, and 424, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:389, 408, and 425, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:390, 183, and 193, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:391, 409, and 426, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:392, 40, and 427, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:394, 39, and 429, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:395, 411, and 430, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:396, 412, and 431, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:396, 412, and 58, respectively;    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs:397, 413, and 432, respectively; or a CDR-L1,        CDR-L2, and CDR-L3 comprising the amino acid sequence of SEQ ID        NOs:398, 414, and 433, respectively.

38. The antibody or antigen-binding fragment of embodiment 36 orembodiment 37, wherein the CDR-L1, CDR-L2, and CDR-L3 are selected from:

-   -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs: 178, 183, and 194, respectively; or    -   a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequence        of SEQ ID NOs: 33, 43, and 421, respectively.

39. The antibody or antigen-binding fragment of any one of embodiments26-36, said antibody or antigen-binding fragment comprises a V_(L)region comprising a CDR-L1, a CDR-L2, and a CDR-L3, respectively,comprising the amino acid sequence of a CDR-L1, a CDR-L2, and a CDR-L3contained within the V_(L) region amino acid sequence selected from anyone of SEQ ID NOs:116-127, 257-267, 534-550 and 552-557.

40. The antibody or antigen-binding fragment thereof of embodiment 39,wherein the CDR-L1, the CDR-L2, and the CDR-L3, respectively, comprisethe amino acid sequence of a CDR-L1, a CDR-L2, and a CDR-L3 containedwithin the V_(L) region amino acid sequence selected from any one of SEQID NOs: 116-118, 120, 121, 124, 125, 258, 262-267 and 534-538.

41. The antibody or antigen-binding fragment thereof of embodiment 39 orembodiment 40, wherein the CDR-L1, the CDR-L2, and the CDR-L3,respectively, comprise the amino acid sequence of a CDR-L1, a CDR-L2,and a CDR-L3 contained within the V_(L) region amino acid sequenceselected from any one of SEQ ID NOs: 267 and 536.

42. The antibody or antigen-binding fragment of any one of embodiments26-39, wherein the V_(L) region comprises a framework region 1 (FR1), aFR2, a FR3, and/or a FR4 having at least 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, or 99% sequence identity, respectively, to a FR1, FR2,FR3, and/or FR4 contained within the V_(L) region amino acid sequenceselected from any one of SEQ ID NOs:116-127, 257-267, 534-550 and552-557.

43. The antibody or antigen-binding fragment of any one of embodiments26-42, wherein the V_(H) region comprises a FR1, a FR2, a FR3, and/or aFR4, selected from:

-   -   a FR1 comprising the amino acid sequence selected from any one        of SEQ ID NOs:72-82, 221-227, 446-459 and 461-466;    -   a FR2 comprising the amino acid sequence selected from any one        of SEQ ID NOs:83-92, 228-232, 467-477 and 479-482;    -   a FR3 comprising the amino acid sequence selected from any one        of SEQ ID NOs:93-101, 233-242, 483-495 and 497-501; and/or a FR4        comprising the amino acid sequence selected from any one of SEQ        ID NOs:102-109, 243-246,502-506 and 508.

44. The antibody or antigen-binding fragment of any one of embodiments26-43, wherein the V_(L) region comprises the amino acid sequenceselected from any one of SEQ ID NOs:116-127, 257-267, 534-550 and552-557.

45. The antibody or antigen-binding fragment thereof of embodiment 44,wherein the V_(L) region comprises the amino acid sequence selected fromany one of SEQ ID NOs: 116-118, 120, 121, 124, 125, 258, 262-267 and534-538.

46. The antibody or antigen-binding fragment thereof of embodiment 44 orembodiment 45, wherein the V_(L) region comprises the amino acidsequence selected from any one of SEQ ID NOs:267 and 536.

47. An antibody or antigen-binding fragment thereof, comprising:

-   -   a heavy chain complementarity determining region 1 (CDR-H1),        CDR-H2, and CDR-H3, respectively, comprising the amino acid        sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the        V_(H) region amino acid sequence selected from any one of SEQ ID        NOs:110-115, 247-256, 518-531 and 533; and/or    -   a light chain complementarity determining region 1 (CDR-L1),        CDR-L2, and CDR-L3, respectively, comprising the amino acid        sequences of CDR-L1, CDR-L2, and CDR-L3 contained within the        V_(L) region amino acid sequence selected from any one of SEQ ID        NOs:116-127, 257-267, 534-550 and 552-557.

48. The antibody or antigen-binding fragment thereof of embodiment 47,wherein the CDR-H1, CDR-H2, and CDR-H3, respectively, comprise the aminoacid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V_(H)region amino acid sequence selected from any one of SEQ ID NOs: 110-113,115, 248, 252-256 and 518-522; and/or

-   -   a light chain complementarity determining region 1 (CDR-L1),        CDR-L2, and CDR-L3, respectively, comprising the amino acid        sequences of CDR-L1, CDR-L2, and CDR-L3 contained within the        V_(L) region amino acid sequence selected from any one of SEQ ID        NOs: 116-118, 120, 121, 124, 125, 258, 262-267 and 534-538.

49. The antibody or antigen-binding fragment thereof of embodiment 47 orembodiment 48, wherein the CDR-H1, CDR-H2, and CDR-H3, respectively,comprise the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs: 115 and 256; and/or

-   -   a light chain complementarity determining region 1 (CDR-L1),        CDR-L2, and CDR-L3, respectively, comprising the amino acid        sequences of CDR-L1, CDR-L2, and CDR-L3 contained within the        V_(L) region amino acid sequence selected from any one of SEQ ID        NOs: 267 and 536.

50. An antibody or antigen-binding fragment thereof, comprising:

-   -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:110 and 116,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:111 and 117,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:110 and 118,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:110 and 119,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:110 and 120,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:110 and 121,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:110 and 122,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:110 and 123,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:112 and 124,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:113 and 125,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:114 and 126,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:115 and 127,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:247 and 257,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:248 and 258,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:249 and 259,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:250 and 260,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:251 and 261,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:252 and 262,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:253 and 263,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:254 and 264,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:255 and 265,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:256 and 266,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:256 and 267,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:518 and 534,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:519 and 535,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:115 and 536,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:520 and 264,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:521 and 537,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:522 and 538,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:523 and 539,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:519 and 540,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:524 and 541,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:525 and 261,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:526 and 542,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:527 and 543,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:528 and 544,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:529 and 545,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:528 and 546,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:522 and 547,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:256 and 548,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:530 and 549,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:531 and 550,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:519 and 552,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:110 and 553,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:110 and 118,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:533 and 554,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:115 and 555,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:524 and 556,        respectively; or    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:519 and 557,        respectively.

51. The antibody or antigen-binding fragment thereof of embodiment 50,comprising:

-   -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOS:110 and 116,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:111 and 117,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:110 and 118,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:110 and 120,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:110 and 121,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:112 and 124,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:113 and 125,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:248 and 258,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:252 and 262,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:253 and 263,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:254 and 264,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:255 and 265,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:256 and 266,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:256 and 267,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:518 and 534,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:519 and 535,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:115 and 536,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:520 and 264,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:521 and 537,        respectively; or    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to and SEQ ID NOs:522 and        538, respectively.

52. The antibody or antigen-binding fragment thereof of embodiment 50 orembodiment 51, comprising:

-   -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOS:256 and 267,        respectively;    -   a V_(H) region and a V_(L) regions comprising the amino acid        sequence having at least 90% identity to SEQ ID NOs:115 and 536,        respectively;    -   53. The antibody or antigen-binding fragment of embodiment 50,        comprising a V_(H) region sequence that is at least at or about        91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to such        a SEQ ID NO and/or a V_(L) region sequence that is at least at        or about 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%        identical to such a SEQ ID NO.

54. The antibody or antigen-binding fragment of embodiment 50 orembodiment 53, wherein:

-   -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:110 and 116, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:111 and 117, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:110 and 118, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:110 and 119, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:110 and 120, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:110 and 121, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:110 and 122, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:110 and 123, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:112 and 124, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:113 and 125, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:114 and 126, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:115 and 127, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:247 and 257, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:248 and 258, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:249 and 259, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:250 and 260, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:251 and 261, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:252 and 262, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:253 and 263, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:254 and 264, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:255 and 265, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:256 and 266, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:256 and 267, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:518 and 534, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:519 and 535, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:115 and 536, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:520 and 264, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:521 and 537, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:522 and 538, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:523 and 539, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:519 and 540, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:524 and 541, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:525 and 261, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:526 and 542, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:527 and 543, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:528 and 544, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:529 and 545, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:528 and 546, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:522 and 547, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:256 and 548, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:530 and 549, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:531 and 550, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:519 and 552, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:110 and 553, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:110 and 118, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:533 and 554, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:115 and 555, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:524 and 556, respectively; or the V_(H) and V_(L) regions of        the antibody or antigen-binding fragment thereof comprise the        amino acid sequences of SEQ ID NOs:519 and 557, respectively.

55. The antibody or antigen-binding fragment thereof of embodiment 50,comprising: the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOS:110 and 116, respectively;

-   -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:111 and 117, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:110 and 118, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:110 and 120, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:110 and 121, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:112 and 124, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:113 and 125, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:248 and 258, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:252 and 262, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:253 and 263, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:254 and 264, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:255 and 265, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:256 and 266, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:256 and 267, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:518 and 534, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:519 and 535, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:115 and 536, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:520 and 264, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:521 and 537, respectively; or    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of and SEQ ID        NOs:522 and 538, respectively.

56. The antibody or antigen-binding fragment thereof of embodiment 54 orembodiment 55, comprising:

-   -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOS:256 and 267, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:115 and 536, respectively;    -   57. The antibody or antigen-binding fragment of any one of        embodiments 1-54, wherein said antibody or antigen-binding        fragment specifically binds to a BCMA protein.

58. The antibody or antigen-binding fragment of embodiment 57, whereinthe BCMA protein is a human BCMA protein, a mouse BCMA protein, or anon-human primate BCMA protein.

59. The antibody or antigen-binding fragment of embodiment 57, whereinthe BCMA protein is a human BCMA protein.

60. The antibody or antigen-binding fragment of any of embodiments 1-59,wherein said antibody or antigen-binding fragment comprises a heavychain complementarity determining region 3 (CDR-H3) comprising the aminoacid sequence selected from any one of SEQ ID NOs: 7 and 157, or aCDR-H3 contained within the heavy chain variable (V_(H)) region aminoacid sequence selected from any one of SEQ ID NOs:110, 256 and 519,and/or

-   -   a light chain complementarity determining region 3 (CDR-L3)        comprising the amino acid sequence selected from any one of SEQ        ID NOs: 47, 51, 194 and 416, or a CDR-L3 contained within the        light chain variable (V_(L)) region amino acid sequence selected        from any one of SEQ ID NOs: 116, 120, 267 and 535.

61. The antibody or antigen-binding fragment of any of embodiments 1-60,wherein said antibody or antigen-binding fragment further comprises:

-   -   a heavy chain complementarity determining region 1 (CDR-H1)        comprising the amino acid sequence selected from any one of SEQ        ID NOs: 1 and 2, or a CDR-H1 contained within the heavy chain        variable (V_(H)) region amino acid sequence selected from any        one of SEQ ID NOs:110, 256 and 519, and/or    -   a light chain complementarity determining region 1 (CDR-L1)        comprising the amino acid sequence selected from any one of SEQ        ID NOs: 26, 30, 178 and 380, or a CDR-L1 contained within the        light chain variable (V_(L)) region amino acid sequence selected        from any one of SEQ ID NOs: 116, 120, 267 and 535;    -   a heavy chain complementarity determining region 2 (CDR-H2)        comprising the amino acid sequence selected from any one of SEQ        ID NOs: 4 or 5, or a CDR-H2 contained within the heavy chain        variable (V_(H)) region amino acid sequence selected from any        one of SEQ ID NOs:110, 256 and 519, and/or    -   a light chain complementarity determining region 2 (CDR-L2)        comprising the amino acid sequence selected from any one of SEQ        ID NOs: 37, 39, 183 or 400, or a CDR-L2 contained within the        light chain variable (V_(L)) region amino acid sequence selected        from any one of SEQ ID NOs: 116, 120, 267 and 535.

62. The antibody or antigen-binding fragment of any of embodiments 1-61,wherein said antibody or antigen-binding fragment comprises a V_(H)region comprising a CDR-H1, a CDR-H2, and a CDR-H3, respectively,comprising the amino acid sequence of a CDR-H1, a CDR-H2, and a CDR-H3contained within the V_(H) region amino acid sequence selected from anyone of SEQ ID NOs: 110, 256 and 519; and/or a V_(L) region comprising aCDR-L1, a CDR-L2, and a CDR-L3, respectively, comprising the amino acidsequence of a CDR-L1, a CDR-L2, and a CDR-L3 contained within the V_(L)region amino acid sequence selected from any one of SEQ ID NOs: 116,120, 267 and 535.

63. The antibody or antigen-binding fragment of any of embodiments 1-62,wherein:

-   -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:110 and 116, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:110 and 120, respectively;    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:256 and 267, respectively; or    -   the V_(H) and V_(L) regions of the antibody or antigen-binding        fragment thereof comprise the amino acid sequences of SEQ ID        NOs:519 and 535, respectively.

64. The antibody or antigen-binding fragment of any of embodiments 1-59,wherein said antibody or antigen-binding fragment comprises a heavychain complementarity determining region 3 (CDR-H3) comprising the aminoacid sequence of SEQ ID NO:10, or a CDR-H3 contained within the heavychain variable (V_(H)) region amino acid sequence of SEQ ID NO:115,and/or

-   -   a light chain complementarity determining region 3 (CDR-L3)        comprising the amino acid sequence of SEQ ID NO:421, or a CDR-L3        contained within the light chain variable (V_(L)) region amino        acid sequence of SEQ ID NO:536.

65. The antibody or antigen-binding fragment of any of embodiments 1-59and 64, wherein said antibody or antigen-binding fragment furthercomprises:

-   -   a heavy chain complementarity determining region 1 (CDR-H1)        comprising the amino acid sequence of SEQ ID NO:2, or a CDR-H1        contained within the heavy chain variable (V_(H)) region amino        acid sequence of SEQ ID NO:115 and/or    -   a light chain complementarity determining region 1 (CDR-L1)        comprising the amino acid sequence selected from any one of SEQ        ID NOs: 33, or a CDR-L1 contained within the light chain        variable (V_(L)) region amino acid sequence selected from any        one of SEQ ID NOs:536; and/or    -   a heavy chain complementarity determining region 2 (CDR-H2)        comprising the amino acid sequence of SEQ ID NO:5, or a CDR-H1        contained within the heavy chain variable (V_(H)) region amino        acid sequence of SEQ ID NO:115 and/or    -   a light chain complementarity determining region 2 (CDR-L2)        comprising the amino acid sequence selected from any one of SEQ        ID NOs:43, or a CDR-L1 contained within the light chain variable        (V_(L)) region amino acid sequence selected from any one of SEQ        ID NOs:536.

66. The antibody or antigen-binding fragment of any of embodiments 1-5964 and 65, wherein said antibody or antigen-binding fragment comprises aV_(H) region comprising a CDR-H1, a CDR-H2, and a CDR-H3, respectively,comprising the amino acid sequence of a CDR-H1, a CDR-H2, and a CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:115;and/or a V_(L) region comprising a CDR-L1, a CDR-L2, and a CDR-L3,respectively, comprising the amino acid sequence of a CDR-L1, a CDR-L2,and a CDR-L3 contained within the V_(L) region amino acid sequence ofSEQ ID NO:536.

67. The antibody or antigen-binding fragment of any of embodiments 1-59and 64, wherein the V_(H) and V_(L) regions of the antibody orantigen-binding fragment thereof comprise the amino acid sequences ofSEQ ID NOs:115 and 536, respectively.

68. The antibody or antigen-binding fragment of any of embodiments 1-59,wherein the antibody or antigen-binding fragment further specificallybinds to mouse BCMA or non-human primate BCMA.

69. The antibody or antigen-binding fragment of any one of embodiments58-68, wherein said human BCMA protein comprises an amino acid sequenceof SEQ ID NO:367 or 368.

70. The antibody or antigen-binding fragment of any one of embodiments1-69, wherein the antibody or antigen-binding fragment is human.

71. The antibody or antigen-binding fragment thereof of any ofembodiments 1-70, wherein the antibody is a human antibody.

72. The antibody or antigen-binding fragment of embodiment 70 orembodiment 71, wherein:

-   -   the antibody or antigen-binding fragment comprises a heavy chain        variable (V_(H)) region, said V_(H) region comprises a portion        having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence        identity to an amino acid sequence encoded by a germline        nucleotide human heavy chain V segment, a portion with at least        95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino        acid sequence encoded by a germline nucleotide human heavy chain        D segment, and/or a portion having at least 95%, 96%, 97%, 98%,        99%, or 100% sequence identity to an amino acid sequence encoded        by a germline nucleotide human heavy chain J segment; and/or    -   the antibody or antigen-binding fragment comprises a light chain        variable (V_(L)) region, said V_(L) region comprises a portion        with at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity        to an amino acid sequence encoded by a germline nucleotide human        kappa or lambda chain V segment, and/or a portion with at least        95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino        acid sequence encoded by a germline nucleotide human kappa or        lambda chain J segment.

73. The antibody or antigen-binding fragment of any one of embodiments70-72, wherein:

-   -   the CDR-H1 and/or CDR-H2 comprises a sequence 100% identical or        with no more than one amino acid difference as compared to an        amino acid sequence of a CDR-H1 and/or CDR-H2, respectively,        within a sequence encoded by a germline nucleotide human heavy        chain V segment; and/or    -   the CDR-L1 and/or CDR-L2 comprises a sequence 100% identical or        with no more than one amino acid difference as compared to an        amino acid sequence of a CDR-L1 and/or CDR-L2, respectively,        within a sequence encoded by a germline nucleotide human kappa        or lambda v segment.

74. The antibody or antigen-binding fragment of any one of embodiments1-73, wherein the antibody or antigen-binding fragment is recombinant.

75. The antibody or antigen-binding fragment of any one of embodiments1-74, wherein the antibody or antigen-binding fragment is monoclonal.

76. The antibody or antigen-binding fragment of any one of embodiments1-75, that is an antigen-binding fragment.

77. The antibody or antigen-binding fragment of any one of embodiments1-76, that is a single chain fragment.

78. The antibody or antigen-binding fragment of any one of embodiments1-77, wherein the V_(H) region is amino-terminal to the V_(L) region.

79. The antibody or antigen-binding fragment of any of embodiments 1-78,wherein the V_(H) region is carboxy-terminal to the V_(L) region.

80. The antibody or antigen-binding fragment of any one of embodiments1-79, that is a fragment comprising antibody V_(H) and V_(L) regionsjoined by a flexible linker.

81. The antibody or antigen-binding fragment of embodiment 77 orembodiment 80, wherein the fragment comprises an scFv.

82. The antibody or antigen-binding fragment of embodiment 81, whereinthe scFv comprises a linker comprising the amino acid sequenceGGGGSGGGGSGGGGS (SEQ ID NO:361).

83. The antibody or antigen-binding fragment of embodiment 81 orembodiment 82, wherein the scFv comprises the amino acid sequenceselected from any one of SEQ ID NOs:128-139, 268-278, 558-576 and578-583, or an amino acid sequence having at least 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acidsequence selected from any one of SEQ ID NOs:128-139, 268-278, 558-576and 578-583.

84. The antibody or antigen-binding fragment of any of embodiments81-83, wherein the scFv comprises the amino acid sequence selected fromany one of SEQ ID NOs: 128, 129, 130, 132, 133, 136, 137, 269, 273, 274,275, 276, 277, 278, 558, 559, 560, 561, 562 and 563, or an amino acidsequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or99% sequence identity to the amino acid sequence selected from any oneof SEQ ID NOs: 128, 129, 130, 132, 133, 136, 137, 269, 273, 274, 275,276, 277, 278, 558, 559, 560, 561, 562 and 563.

85. The antibody or antigen-binding fragment of any of embodiments81-84, wherein the scFv comprises the amino acid sequence selected fromany one of SEQ ID NOs: 278 and 560, or an amino acid sequence having atleast 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequenceidentity to the amino acid sequence selected from any one of SEQ ID NOs:278 and 560.

86. A single chain cell-surface protein, comprising the antibody orantigen-binding fragment of any one of embodiments 1-85.

87. A single chain cell surface protein comprising the scFv amino acidsequence selected from any one of SEQ ID NOs:128-139, 268-278, 558-576and 578-583 or comprising the V_(H) region amino acid sequence selectedfrom any one of SEQ ID NOs:110-115, 247-256, 518-531 and 533.

88. The single chain cell surface protein of embodiment 87, wherein thescFv comprises the amino acid sequence selected from any one of SEQ IDNOs: 128, 129, 130, 132, 133, 136, 137, 269, 273, 274, 275, 276, 277,278, 558, 559, 560, 561, 562 and 563.

89. The single chain cell surface protein of embodiment 87 or embodiment88, wherein the scFv comprises the amino acid sequence selected from anyone of SEQ ID NOs: 278 and 560.

90. The antibody or antigen-binding fragment of any one of embodiments1-87, which further comprises at least a portion of an immunoglobulinconstant region.

91. The antibody or antigen-binding fragment of embodiment 90, whereinthe portion of an immunoglobulin constant region comprises at least aportion of the hinge region.

92. The antibody or antigen-binding fragment of embodiment 90, whereinthe portion of an immunoglobulin constant region comprises an Fc region.

93. The antibody or antigen-binding fragment of embodiment 92, whereinthe Fc region is an Fc region of a human IgG.

94. A conjugate, comprising the antibody or antigen-binding fragment ofany one of embodiments 1-98 and a heterologous molecule or moiety.

95. A chimeric antigen receptor (CAR) comprising an extracellularportion comprising the antibody or antigen-binding fragment of any oneof embodiments 1-93 and an intracellular signaling region.

96. The chimeric antigen receptor of embodiment 95, wherein the antibodyor antigen-binding fragment comprises an sdAb comprising only the V_(H)region or an scFv and the intracellular signaling region comprises anintracellular signaling domain.

97. The chimeric antigen receptor of embodiment 96, wherein theintracellular signaling domain is or comprises a primary signalingdomain, a signaling domain that is capable of inducing a primaryactivation signal in a T cell, a signaling domain of a T cell receptor(TCR) component, and/or a signaling domain comprising an immunoreceptortyrosine-based activation motif (ITAM).

98. The chimeric antigen receptor of embodiment 97, wherein theintracellular signaling domain is or comprises an intracellularsignaling domain of a CD3 chain, optionally a CD3-zeta (CD3ζ) chain, ora signaling portion thereof.

99. The chimeric antigen receptor of any of embodiments 95-98, whereinthe recombinant receptor further comprises a transmembrane domaindisposed between the extracellular domain and the intracellularsignaling region.

100. The chimeric antigen receptor of embodiment 99, wherein thetransmembrane domain comprises a transmembrane portion of CD28.

101. The chimeric antigen receptor of any of embodiments 95-100, whereinthe intracellular signaling region further comprises a costimulatorysignaling domain.

102. The chimeric antigen receptor of embodiment 101, wherein thecostimulatory signaling domain comprises an intracellular signalingdomain of a T cell costimulatory molecule or a signaling portionthereof.

103. The chimeric antigen receptor of embodiment 101 or embodiment 102,wherein the costimulatory signaling domain comprises an intracellularsignaling domain of a CD28, a 4-1BB or an ICOS or a signaling portionthereof.

104. The chimeric antigen receptor of any of embodiments 101-103,wherein the costimulatory signaling domain is between the transmembranedomain and the intracellular signaling domain.

105. A polynucleotide encoding the antibody or antigen-binding fragmentthereof of any one of embodiments 1-93, conjugate of embodiment 94 orthe chimeric antigen receptor of any one of embodiments 95-104.

106. The polynucleotide of embodiment 105, further encoding a GM-CSFsignal sequence, a CD8 signal sequence, an Ig kappa signal sequence or aCD33 signal sequence.

107. A vector, comprising the polynucleotide of embodiment 105 orembodiment 106.

108. The vector of embodiment 107, wherein the vector is an expressionvector.

109. The vector of embodiment 107 or embodiment 108, wherein the vectoris a viral vector.

110. The vector of embodiment 109, wherein the viral vector is aretroviral vector.

111. The vector of embodiment 109 or embodiment 110, wherein the viralvector is a lentiviral vector.

112. The vector of embodiment 111, wherein the lentiviral vector isderived from HIV-1.

113. An engineered cell comprising the vector of any one of embodiments107-112.

114. An engineered cell expressing a receptor comprising the antibody orantigen-binding fragment of any one of embodiments 1-93, conjugate ofembodiment 94 or the chimeric antigen receptor of any one of embodiments95-102.

115. The engineered cell of embodiment 114 or embodiment 115, whereinthe engineered cell is a T cell.

116. A composition comprising the antibody or antigen-binding fragmentthereof of any one of embodiments 1-93, conjugate of embodiment 94, thechimeric antigen receptor of any one of embodiments 95-102, or the cellof any one of embodiments 113-115.

117. The composition of embodiment 116, further comprising apharmaceutically acceptable excipient.

118. A method of treatment, comprising administering the composition ofembodiment 116 or embodiment 117 to a subject having a disease ordisorder associated with BCMA.

119. A method of treatment, comprising administering an antibody orantigen-binding fragment of any one of embodiments 1-93, conjugate ofembodiment 94, the chimeric antigen receptor of any one of embodiments95-102, or the cell of any one of embodiments 113-115 to a subjecthaving a disease or disorder associated with BCMA.

120. The method of embodiment 118 or embodiment 119, wherein the diseaseor disorder associated with BCMA is associated with BCMA expression.

121. The method of any one of embodiments 118-120, wherein the diseaseor disorder associated with BCMA is a B cell-related disorder.

122. The method of any one of embodiments 118-121, wherein the diseaseor disorder associated with BCMA is an autoimmune disease or disorder.

123. The method of embodiment 122, wherein the autoimmune disease ordisorder is systemic lupus erythematosus (SLE), lupus nephritis,inflammatory bowel disease, rheumatoid arthritis, ANCA associatedvasculitis, idiopathic thrombocytopenia purpura (ITP), thromboticthrombocytopenia purpura (TTP), autoimmune thrombocytopenia, Chagas'disease, Grave's disease, Wegener's granulomatosis, poly-arteritisnodosa, Sjogren's syndrome, pemphigus vulgaris, scleroderma, multiplesclerosis, psoriasis, IgA nephropathy, IgM polyneuropathies, vasculitis,diabetes mellitus, Reynaud's syndrome, anti-phospholipid syndrome,Goodpasture's disease, Kawasaki disease, autoimmune hemolytic anemia,myasthenia gravis, or progressive glomerulonephritis.

124. The method of any one of embodiments 118-121, wherein the diseaseor disorder associated with BCMA is a cancer.

125. The method of embodiment 124, wherein the cancer is aBCMA-expressing cancer.

126. The method of embodiment 124 or embodiment 125, wherein the canceris a B cell malignancy.

127. The method of any one of embodiments 124-126, wherein the cancer isa lymphoma, a leukemia, or a plasma cell malignancy.

128. The method of embodiment 127, wherein the lymphoma is Burkitt'slymphoma, non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma, Waldenstrommacroglobulinemia, follicular lymphoma, small non-cleaved cell lymphoma,mucosa-associated lymphatic tissue lymphoma (MALT), marginal zonelymphoma, splenic lymphoma, nodal monocytoid B cell lymphoma,immunoblastic lymphoma, large cell lymphoma, diffuse mixed celllymphoma, pulmonary B cell angiocentric lymphoma, small lymphocyticlymphoma, primary mediastinal B cell lymphoma, lymphoplasmacyticlymphoma (LPL), or mantle cell lymphoma (MCL).

129. The method of embodiment 127, wherein the leukemia is chroniclymphocytic leukemia (CLL), plasma cell leukemia or acute lymphocyticleukemia (ALL).

130. The method of embodiment 127, wherein the plasma cell malignancy ismultiple myeloma (MM) or plasmacytoma.

131. A composition of embodiment 116 or embodiment 117 for use intreating a disease or disorder associated with BCMA.

132. Use of a composition of embodiment 116 or embodiment 117 for themanufacture of a medicament for treating a disease or disorderassociated with BCMA.

133. The composition for use or use of embodiment 132, wherein thedisease or disorder associated with BCMA is associated with BCMAexpression.

134. The composition for use or use of any one of embodiments 131-133,wherein the disease or disorder associated with BCMA is a B cell-relateddisorder.

135. The composition for use or use of any one of embodiments 131-134,wherein the disease or disorder associated with BCMA is an autoimmunedisease or disorder.

136. The composition for use or use of 135, wherein the autoimmunedisease or disorder is systemic lupus erythematosus (SLE), lupusnephritis, inflammatory bowel disease, rheumatoid arthritis, ANCAassociated vasculitis, idiopathic thrombocytopenia purpura (ITP),thrombotic thrombocytopenia purpura (TTP), autoimmune thrombocytopenia,Chagas' disease, Grave's disease, Wegener's granulomatosis,poly-arteritis nodosa, Sjogren's syndrome, pemphigus vulgaris,scleroderma, multiple sclerosis, psoriasis, IgA nephropathy, IgMpolyneuropathies, vasculitis, diabetes mellitus, Reynaud's syndrome,anti-phospholipid syndrome, Goodpasture's disease, Kawasaki disease,autoimmune hemolytic anemia, myasthenia gravis, or rapidly progressiveglomerulonephritis.

137. The composition for use or use of any one of embodiments 131-134,wherein the disease or disorder associated with BCMA is a cancer.

138. The composition for use or use of embodiment 137, wherein thecancer is a BCMA-expressing cancer.

139. The composition for use or use of embodiment 137 or embodiment 138,wherein the cancer is a B cell malignancy.

140. The composition for use or use of embodiments 137-139, wherein thecancer is a lymphoma, a leukemia, or a plasma cell malignancy.

141. The composition for use or use of embodiment 140, wherein thelymphoma is Burkitt's lymphoma, non-Hodgkin's lymphoma (NHL), Hodgkin'slymphoma, Waldenstrom macroglobulinemia, follicular lymphoma, smallnon-cleaved cell lymphoma, mucosa-associated lymphatic tissue lymphoma(MALT), marginal zone lymphoma, splenic lymphoma, nodal monocytoid Bcell lymphoma, immunoblastic lymphoma, large cell lymphoma, diffusemixed cell lymphoma, pulmonary B cell angiocentric lymphoma, smalllymphocytic lymphoma, primary mediastinal B cell lymphoma,lymphoplasmacytic lymphoma (LPL), or mantle cell lymphoma (MCL).

142. The composition for use or use of embodiment 140, wherein theleukemia is chronic lymphocytic leukemia (CLL), plasma cell leukemia oracute lymphocytic leukemia (ALL).

143. The composition for use or use of embodiment 140, wherein theplasma cell malignancy is multiple myeloma (MM) or plasmacytoma.

V. EXAMPLES

The following examples are included for illustrative purposes only andare not intended to limit the scope of the invention.

Example 1: Generation and Assessment of Anti-BCMA Antibodies (V_(H)Chain Only)

Exemplary anti-BCMA antibodies containing a heavy chain variable (V_(H))region that specifically bound to BCMA, even in the absence of a lightchain variable (V_(L)) region, were generated and assessed.

1A. Library Selection and Antibody Generation

A number of BCMA-binding V_(H) regions were generated through a seriesof selection steps carried out on members of a dsDNA-encoded His-taggedhuman normal donor antibody V_(H) library displayed in a cell-freesystem. Members of the V_(H) library were subjected to multiple roundsof screening to select V_(H) regions that bound specifically to solublehuman BCMA fused to an immunoglobulin Fc region (hBCMA-Fc). V_(H)regions from selected hBCMA-Fc pools were screened, by flow cytometryusing a fluorochrome-conjugated anti-HIS antibody, for binding to arecombinant HEK293 cell line expressing human BCMA (hBCMA/HEK293 cellline), as compared to the parental HEK293 cell line not expressing BCMA,as well as to for binding to a human myeloma cell line expressingendogenous BCMA (H929 cells). The results identified V_(H) region clonesthat exhibited specific binding to hBCMA/HEK293 cells and, to a lesserdegree, to H929 cells.

Exemplary V_(H) clones exhibiting specific binding to cell linesexpressing BCMA but not to BCMA-negative control cells were sequencedand purified for further characterization. Clones were purified andtitrated, and their binding affinities (EC₅₀) to hBCMA/HEK293 cells weremeasured using a flow cytometry-based assay with thefluorochrome-conjugated anti-HIS-antibody. Table 3 lists heavy chaincomplementarity determining region 3 (CDR-H3) sequences of exemplaryclones, containing human V_(H)3-derived framework regions and theirrespective binding affinities (EC₅₀) observed in this study.

TABLE 3 CDR3 amino acid sequences for representative V_(H) clones V_(H)Heavy Chain Clone CDR3 sequence CDR-H3 Sequence EC₅₀ Name (CDR-H3)ªIdentifier Number (nM)^(b) V_(H)-1 VDGPPSFDI SEQ ID NO: 10 >100 V_(H)-2WSAPTDY SEQ ID NO: 7   25 V_(H)-3 VDGDDAFDI SEQ ID NO: 279 >100 V_(H)-4DPLSWDSSGKGPR SEQ ID NO: 280  100 V_(H)-5 ENYDFWSWRYYYDMDVSEQ ID NO: 281 >100 V_(H)-6 VDGPPSYDI SEQ ID NO: 282 >100 V_(H)-7GDWDDAFDI SEQ ID NO: 283 >100 V_(H)-8 VDGDYVDDY SEQ ID NO: 9 ND V_(H)-9VDGDYEDY SEQ ID NO: 284 >100 V_(H)-10 DVPSSGDDAFDI SEQ ID NO: 285 >100V_(H)-11 VDGDDVFDI SEQ ID NO: 286 >100 V_(H)-12 VDGDAFDI SEQ ID NO: 287 100 ^(a)Amino acid sequences shown according to Kabat numbering. ^(b)NDindicates not detected

Example 2: Generation and Assessment of Anti-BCMA Antibodies (scFvs)

Exemplary anti-BCMA antibodies, formatted as single chain antibodyfragments (scFvs), were identified and assessed for binding to BCMA.

2A. Library Selection and scFv Antibody Generation

Exemplary anti-BCMA scFv antibodies were generated through variousselections, carried out on dsDNA-encoded human normal donor antibodylibraries displayed in a cell-free system. In one approach, V_(H) regionlibrary members enriched from a first round of screening in the approachdescribed in Example 1 were paired by shuffling with members of a humannormal donor V_(L) library, to generate an scFv library, inV_(H)-(G₄S)₃-V_(L) format. The resulting scFv libraries were enriched insubsequent rounds of selection for specific binding to BCMA-expressingHEK293 cells as compared to parental HEK293 cells.

In another approach, de novo selection was carried out by screening anormal donor-derived human scFv library for BCMA-specific binding tohBCMA-Fc in the presence or absence of competitive elution with a mouseanti-BCMA reference scFv antibody (either BCMA-C1, V_(L)-V_(H) scFvantibody, SEQ ID NO:328; or BCMA-C2, scFv antibody, SEQ ID NO:329).After at least 2 rounds of selection, scFv binders were recovered.

Specific binding of resulting scFv clones to BCMA-expressing HEK293cells, as compared to control cells not expressing BCMA, was assessed byflow cytometry either with in vitro translated crude cell lysate or withbacterially-produced supernatant. Certain scFv clones displaying bindingpreference for BCMA were further analyzed.

The selected scFv clones were sequenced using forward and reverseprimers and purified for further characterization. Table 4 listssequence identifiers (SEQ ID NO) corresponding to amino acid (aa) andnucleotide (nt) sequences of the scFv and amino acid sequences of thecorresponding heavy chain (V_(H)) or light chain (V_(L)) variableregions, CDRs and framework regions (FRs). With respect to cloneBCMA-22, the first residue of light chain CDR3 (a cysteine), which wasobserved to have been inherited from the germline framework region wasreplaced with a serine to generate an additional scFv, designatedBCMA-23. Table 4 also sets forth the sequence of exemplary mouseanti-BCMA reference antibodies used as controls and in competitionstudies as described in subsequent Examples.

TABLE 4 Sequence identifier (SEQ ID NO) for Exemplary Clones andReference Antibody Heavy Chain Light Chain V_(H) FR V_(L) FR (FR1, 2,(FR1, 2, CDR-H1, CDR-H2, 3, 4 CDR-L1, CDR-L2, 3, 4, scFv Clone # V_(H)CDR-H3 Kabat) V_(L) CDR-L3 Kabat) aa nt BCMA- 110 1, 4, 7 (Kabat) 59,64, 116 26, 37, 47 (Kabat) 72, 83, 128 330 1 12, 16, 7 (Chothia) 67, 7026, 37, 47 (Chothia) 93, 102 19, 23, 7 (AbM) 26, 37, 47 (AbM) BCMA- 1112, 5, 8 (Kabat) 60, 65, 117 27, 38, 48 (Kabat) 73, 84, 129 331 2 13, 17,8 (Chothia) 68, 71 27, 38, 48 (Chothia) 94, 103 20, 24, 8 (AbM) 27, 38,48 (AbM) BCMA- 110 1, 4, 7 (Kabat) 59, 64, 118 28, 39, 49 (Kabat) 74,85, 130 332 3 12, 16, 7 (Chothia) 67, 70 28, 39, 49 (Chothia) 93, 10419, 23, 7 (AbM) 28, 39, 49 (AbM) BCMA- 110 1, 4, 7 (Kabat) 59, 64, 11929, 40, 50 (Kabat) 75, 86, 131 333 4 12, 16, 7 (Chothia) 67, 70 29, 40,50 (Chothia) 95, 104 19, 23, 7 (AbM) 29, 40, 50 (AbM) BCMA- 110 1, 4, 7(Kabat) 59, 64, 120 30, 39, 51 (Kabat) 76, 85, 132 334 5 12, 16, 7(Chothia) 67, 70 30, 39, 51 (Chothia) 93, 105 19, 23, 7 (AbM) 30, 39, 51(AbM) BCMA- 110 1, 4, 7 (Kabat) 59, 64, 121 31, 41, 52 (Kabat) 77, 87,133 335 6 12, 16, 7 (Chothia) 67, 70 31, 41, 52 (Chothia) 96, 104 19,23, 7 (AbM) 31, 41, 52 (AbM) BCMA- 110 1, 4, 7 (Kabat) 59, 64, 122 32,42, 53 (Kabat) 78, 88, 134 336 7 12, 16, 7 (Chothia) 67, 70 32, 42, 53(Chothia) 97, 106 19, 23, 7 (AbM) 32, 42, 53 (AbM) BCMA- 110 1, 4, 7(Kabat) 59, 64, 123 30, 39, 54 (Kabat) 76, 85, 135 337 8 12, 16, 7(Chothia) 67, 70 30, 39, 54 (Chothia) 93, 107 19, 23, 7 (AbM) 30, 39, 54(AbM) BCMA- 112 2, 5, 9 (Kabat) 61, 65, 124 33, 43, 55 (Kabat) 79, 89,136 338 9 13, 17, 9 (Chothia) 69, 70 33, 43, 55 (Chothia) 98, 108 20,24, 9 (AbM) 33, 43, 55 (AbM) BCMA- 113 2, 5, 10 (Kabat) 62, 65, 125 34,44, 56 (Kabat) 80, 90, 137 339 10 14, 17, 10 (Chothia) 68, 71 34, 44, 56(Chothia) 99, 108 21, 24, 10 (AbM) 34, 44, 56 (AbM) BCMA- 114 3, 6, 11(Kabat) 63, 66, 126 35, 45, 57 (Kabat) 81, 91, 138 340 11 15, 18, 11(Chothia) 69, 71 35, 45, 57 (Chothia) 100, 108 22, 25, 11 (AbM) 35, 45,57 (AbM) BCMA- 115 2, 5, 10 (Kabat) 60, 65, 127 36, 46, 58 (Kabat) 82,92, 139 341 12 13, 17, 10 (Chothia) 68, 71 36, 46, 58 (Chothia) 101, 10920, 24, 10 (AbM) 36, 46, 58 (AbM) BCMA- 247 140, 145, 149 (Kabat) 195,204, 257 174, 179, 184 (Kabat) 221, 228, 268 342 13 158, 161, 149(Chothia) 210, 217 174, 179, 184 (Chothia) 233, 243 165, 170, 149 (AbM)174, 179, 184 (AbM) BCMA- 248 141, 145, 149 (Kabat) 196, 204, 258 174,179, 185 (Kabat) 221, 228, 269 343 14 158, 161, 149 (Chothia) 211, 218174, 179, 185 (Chothia) 234, 109 166, 170, 149 (AbM) 174, 179, 185 (AbM)BCMA- 249 141, 145, 150 (Kabat) 197, 204, 259 174, 179, 186 (Kabat) 222,228, 270 344 15 158, 161, 150 (Chothia) 212, 70 174, 179, 186 (Chothia)235, 109 166, 170, 150 (AbM) 174, 179, 186 (AbM) BCMA- 250 142, 146, 151(Kabat) 198, 205, 260 174, 179, 187 (Kabat) 223, 228, 271 345 16 159,162, 151 (Chothia) 213, 70 174, 179, 187 (Chothia) 235, 109 167, 171,151 (AbM) 174, 179, 187 (AbM) BCMA- 251 2, 5, 152 (Kabat) 199, 206, 261175, 180, 188 (Kabat) 224, 229, 272 346 17 13, 17, 152 (Chothia) 69, 219175, 180, 188 (Chothia) 237, 109 20, 24, 152 (AbM) 175, 180, 188 (AbM)BCMA- 252 143, 147, 153 (Kabat) 200, 207, 262 174, 179, 189 (Kabat) 222,228, 273 347 18 158, 163, 153 (Chothia) 214, 70 174, 179, 189 (Chothia)238, 109 168, 172, 153 (AbM) 174, 179, 189 (AbM) BCMA- 253 144, 148, 154(Kabat) 201, 208, 263 176, 181, 190 (Kabat) 225, 230, 274 348 19 160,164, 54 (Chothia) 215, 220 176, 181, 190 (Chothia) 239, 244 169, 173,154 (AbM) 176, 181, 190 (AbM) BCMA- 254 3, 6, 155 (Kabat) 202, 209, 264177, 182, 191 (Kabat) 226, 231, 275 349 20 15, 18, 155 (Chothia) 216, 70177, 182, 191 (Chothia) 240, 245 22, 25, 155 (AbM) 177, 182, 191 (AbM)BCMA- 255 2, 5, 156 (Kabat) 203, 65, 265 174, 179, 192 (Kabat) 222, 228,276 350 21 13, 17, 156 (Chothia) 68, 70 174, 179, 192 (Chothia) 241, 24620, 24, 156 (AbM) 174, 179, 192 (AbM) BCMA- 256 2, 5, 157 (Kabat) 60,65, 266 178, 183, 193 (Kabat) 227, 232, 277 351 22 13, 17, 157 (Chothia)68, 70 178, 183, 193 (Chothia) 242, 246 20, 24, 157 (AbM) 178, 183, 193(AbM) BCMA- 256 2, 5, 157 (Kabat) 60, 65, 267 178, 183, 194 (Kabat) 227,232, 278 352 23 13, 17, 157 (Chothia) 68, 70 178, 183, 194 (Chothia)242, 246 20, 24, 157 (AbM) 178, 183, 194 (AbM) BCMA- 518 2, 6, 376(Kabat) 61, 65, 534 30, 399, 415 (Kabat) 76, 85, 558 24 13, 18, 376(Chothia) 69, 71 30, 399, 415 (Chothia) 483, 508 20, 25, 376 (AbM) 30,399, 415 (AbM) BCMA- 519 1, 4, 7 (Kabat) 436, 64, 535 380, 400, 416(Kabat) 446, 467, 559 25 12, 16, 7 (Chothia) 67, 70 380, 400, 416(Chothia) 484, 502 19, 23, 7 (AbM) 380, 400, 416 (AbM) BCMA- 115 2, 5,10 (Kabat) 60, 65, 536 33, 43, 421 (Kabat) 80, 89, 560 26 13, 17, 10(Chothia) 68, 71 33, 43, 421 (Chothia) 98, 108 20, 24, 10 (AbM) 33, 43,421 (AbM) BCMA- 520 3, 6, 155 (Kabat) 434, 209, 264 177, 182, 191(Kabat) 226, 231, 561 27 15, 18, 155 (Chothia) 216, 70 177, 182, 191(Chothia) 240, 245 22, 25, 155 (AbM) 177, 182, 191 (AbM) BCMA- 521 3,372, 376 (Kabat) 63, 209, 537 381, 401, 417 (Kabat) 447, 468, 562 28 15,514, 376 (Chothia) 69, 444 381, 401, 417 (Chothia) 485, 508 22, 510, 376(AbM) 381, 401, 417 (AbM) BCMA- 522 3, 6, 376 (Kabat) 63, 209, 538 382,402, 418 (Kabat) 448, 469, 563 29 15, 18, 376 (Chothia) 69, 71 382, 402,418 (Chothia) 486, 503 22, 25, 376 (AbM) 382, 402, 418 (AbM) BCMA- 5233, 6, 377 (Kabat) 435, 209, 539 383, 403, 419 (Kabat) 449, 470, 564 3012, 18, 377 (Chothia) 69, 71 383, 403, 419 (Chothia) 487, 104 509, 25,377 (AbM) 383, 403, 419 (AbM) BCMA- 519 1, 4, 7 (Kabat) 436, 64, 540384, 39, 54 (Kabat) 450, 471, 565 31 12, 16, 7 (Chothia) 67, 70 384, 39,54 (Chothia) 93, 504 19, 23, 7 (AbM) 384, 39, 54 (AbM) BCMA- 524 2, 5,10 (Kabat) 437, 65, 541 385, 180, 58 (Kabat) 451, 472, 566 32 13, 17, 10(Chothia) 68, 71 385, 180, 58 (Chothia) 488, 109 20, 24, 10 (AbM) 385,180, 58 (AbM) BCMA- 525 2, 373, 152 (Kabat) 199, 65, 261 175, 180, 188(Kabat) 224, 229, 567 33 13, 515, 152 (Chothia) 69, 219 175, 180, 188(Chothia) 237, 109 20, 511, 152 (AbM) 175, 180, 188 (AbM) BCMA- 526 3,6, 11 (Kabat) 438, 209, 542 386, 404, 420 (Kabat) 452, 84, 568 34 15,18, 11 (Chothia) 69, 71 386, 404, 420 (Chothia) 489, 504 22, 25, 11(AbM) 386, 404, 420 (AbM) BCMA- 527 2, 5, 378 (Kabat) 61, 65, 543 33,43, 421 (Kabat) 453, 89, 569 35 13, 17, 378 (Chothia) 69, 70 33, 43, 421(Chothia) 98, 505 20, 24, 378 (AbM) 33, 43, 421 (AbM) BCMA- 528 2, 5, 9(Kabat) 199, 65, 544 387, 405, 422 (Kabat) 454, 473, 570 36 13, 17, 9(Chothia) 69, 70 387, 405, 422 (Chothia) 490, 109 20, 24, 9 (AbM) 387,405, 422 (AbM) BCMA- 529 2, 5, 9 (Kabat) 61, 65, 545 388, 406, 423(Kabat) 455, 474, 571 37 13, 17, 9 (Chothia) 441, 70 388, 406, 423(Chothia) 491, 109 20, 24, 9 (AbM) 388, 406, 423 (AbM) BCMA- 528 2, 5, 9(Kabat) 199, 65, 546 388, 407, 424 (Kabat) 456, 474, 572 38 13, 17, 9(Chothia) 69, 70 388, 407, 424 (Chothia) 492, 109 20, 24, 9 (AbM) 388,407, 424 (AbM) BCMA- 522 3, 6, 376 (Kabat) 63, 209, 547 389, 408, 425(Kabat) 457, 475, 573 39 15, 18, 376 (Chothia) 69, 71 389, 408, 425(Chothia) 493, 103 22, 25, 376 (AbM) 389, 408, 425 (AbM) BCMA- 256 2, 5,157 (Kabat) 60, 65, 548 390, 183, 193 (Kabat) 227, 232, 574 40 13, 17,157 (Chothia) 68, 70 390, 183, 193 (Chothia) 242, 108 20, 24, 157 (AbM)390, 183, 193 (AbM) BCMA- 530 2, 374, 9 (Kabat) 199, 65, 549 391, 409,426 (Kabat) 458, 476, 575 584 41 13, 516, 9 (Chothia) 68, 70 391, 409,426 (Chothia) 494, 109 20, 512, 9 (AbM) 391, 409, 426 (AbM) BCMA- 531 1,4, 7 (Kabat) 439, 64, 550 392, 40, 427 (Kabat) 459, 477, 576 42 12, 16,7 (Chothia) 67, 70 392, 40, 427 (Chothia) 495, 506 19, 23, 7 (AbM) 392,40, 427 (AbM) BCMA- 519 1, 4, 7 (Kabat) 436, 64, 552 394, 39, 429(Kabat) 461, 85, 578 44 12, 16, 7 (Chothia) 67, 70 394, 39, 429(Chothia) 93, 107 19, 23, 7 (AbM) 394, 39, 429 (AbM) BCMA- 110 1, 4, 7(Kabat) 59, 64, 553 395, 411, 430 (Kabat) 462, 479, 579 45 12, 16, 7(Chothia) 67, 70 395, 411, 430 (Chothia) 497, 105 19, 23, 7 (AbM) 395,411, 430 (AbM) BCMA- 110 1, 4, 7 (Kabat) 59, 64, 118 28, 39, 49 (Kabat)74, 85, 130 46 12, 16, 7 (Chothia) 67, 70 28, 39, 49 (Chothia) 93, 10419, 23, 7 (AbM) 28, 39, 49 (AbM) BCMA- 533 2, 5, 10 (Kabat) 197, 65, 554396, 412, 431 (Kabat) 463, 480, 580 47 13, 17, 10 (Chothia) 443, 445396, 412, 431 (Chothia) 498, 108 20, 24, 10 (AbM) 396, 412, 431 (AbM)BCMA- 115 2, 5, 10 (Kabat) 60, 65, 555 396, 412, 58 (Kabat) 464, 480,581 48 13, 17, 10 (Chothia) 68, 71 396, 412, 58 (Chothia) 499, 109 20,24, 10 (AbM) 396, 412, 58 (AbM) BCMA- 524 2, 5, 10 (Kabat) 437, 65, 556397, 413, 432 (Kabat) 465, 481, 582 49 13, 17, 10 (Chothia) 68, 71 397,413, 432 (Chothia) 500, 109 20, 24, 10 (AbM) 397, 413, 432 (AbM) BCMA-519 1, 4, 7 (Kabat) 436, 64, 557 398, 414, 433 (Kabat) 466, 482, 583 5112, 16, 7 (Chothia) 67, 70 398, 414, 433 (Chothia) 501, 508 19, 23, 7(AbM) 398, 414, 433 (AbM) BCMA- 324 288, 290, 292 (Kabat) 308, 310, 326302, 304, 306 (Kabat) 316, 318, 585 C1, V_(H)- 294, 296, 292 (Chothia)312, 314 302, 304, 306 (Chothia) 320, 322 V_(L) 298, 300, 292 (AbM) 302,304, 306 (AbM) BCMA- 324 288, 290, 292 (Kabat) 308, 310, 326 302, 304,306 (Kabat) 316, 318, 328 C1, V_(L)- 294, 296, 292 (Chothia) 312, 314302, 304, 306 (Chothia) 320, 322 V_(H) 298, 300, 292 (AbM) 302, 304, 306(AbM) BCMA- 325 289, 291, 293 (Kabat) 309, 311, 327 303, 305, 307(Kabat) 317, 319, 329 C2, V_(H)- 295, 297, 293 (Chothia) 313, 315 303,305, 307 (Chothia) 321, 323 V_(L) 299, 301, 293 (AbM) 303, 305, 307(AbM) BCMA- 325 289, 291, 293 (Kabat) 309, 311, 327 303, 305, 307(Kabat) 317, 319, 586 C2, V_(L)- 295, 297, 293 (Chothia) 313, 315 303,305, 307 (Chothia) 321, 323 V_(H) 299, 301, 293 (AbM) 303, 305, 307(AbM)

2B. Binding Affinities

Clones were purified and titrated, and their binding affinities (EC₅₀)to hBMCA-expressing HEK293 cells was assessed using a flowcytometry-based assay using the fluorochrome-conjugated detectionantibody as described in Example 1. EC₅₀ for mouse anti-BCMA antibodies,either BCMA-C1, V_(L)-V_(H) scFv antibody (SEQ ID NO:328) or BCMA-C2,V_(H)-V_(L) scFv antibody (SEQ ID NO:329), were also determined.

2C. Binding Selectivity

Binding of exemplary scFv clones to hBMCA-expressing HEK293 cells wasassessed and binding was compared to parental HEK293 cells. The resultsshowed that clones exhibited binding selectivity to hBMCA-expressingHEK293 cells over parental HEK293 cells. As an example, clones BCMA-18,-19, -20, -21 and -22 exhibited 2.2-fold, 4.2-fold, 10.8-fold, 3.4-foldand 7.5-fold selective binding, respectively.

Binding of exemplary scFv clones to hBMCA-overexpressing HEK293 cells ascompared to OPM2 and RPMI-8226 cell lines that express moderate levelsof endogenous BCMA was assessed. The results showed that many of thetested clones exhibited higher binding to hBMCA-expressing HEK293 cells,which express a high level of BCMA, compared to the OPM2 and RPMI-8226cell lines that express moderate levels of BCMA. For example, clonesBCMA-1, -2, -3, -4, -5, -7, -8, -9, -10, -12, -18, -19, -20, -21, -22,-30, -31 and -32 exhibited higher binding to hBCMA-overexpressing HEK293cells. In this particular experiment, BCMA-13, -14 and -16 did notexhibit substantially higher binding to hBCMA-expressing HEK293 cellscompared to negative control.

Example 3: Generation and Assessment of Anti-BCMA Antibodies (scFvs)

Epitopes recognized, e.g., specifically bound to, by exemplary anti-BCMAscFv clones (BCMA-1, BCMA-5, BCMA-9, BCMA-23, BCMA-25, BCMA-26, BCMA-52and BCMA-55 anti-BCMA scFvs), were assessed using full discontinuousepitope mapping by Chemical Linkage of Peptides onto Scaffolds (CLIPS;Pepscan Presto BV, Lelystad, The Netherlands; see, e.g., Timmerman etal., (2007) J. Mol. Recognit. 20: 283-329). Mapping was carried outusing anti-BCMA scFv clones, such as those fused with mouse Fc(scFv-mFc).

Linear and conformational peptide libraries of amino acid residues 1-54of human BCMA (set forth as amino acid residues 1-54 of SEQ ID NO:367)were generated based on a combinatorial matrix design. Linear peptidesand structural mimetics including single loop, α-helix, (3-turn,combinatorial and linear disulfide bridge mimics, and discontinuousepitope mimics were used, along with positive and negative controlpeptides, on an amino-functionalized solid support.

Affinities for binding to the peptides in the epitope library weredetermined using ELISA. The peptide arrays were incubated with asolution containing the scFv overnight at 4° C. Affinity information wasused in iterative screens to define the sequence and conformation ofepitopes. Heat maps of affinity information for two or more loops weregenerated.

scFvs assessed were observed to recognized conformational epitopes thatincluded several discontinuous peptide stretches of the BCMA peptidesequence. BCMA-1, BCMA-5, BCMA-23 and BCMA-25 scFv were observed to bindto a peptide of ₃₀SNTPPLTCQR₃₉ (set forth in SEQ ID NO:608), which couldbe recognized in a linear form. In some aspects, such antibodiesrecognize a non-linear or linear epitope including residues of suchpeptide of SEQ ID NO: 608, and in some aspects to recognize a non-linearepitope further including residues of ₂₁CIPCQLR₂₇ (set forth in SEQ IDNO:609), ₃₀SNTPPLTCQR₃₉ (SEQ ID NO: 608) and/or ₄₄SVTNSVK₅₀ (set forthin SEQ ID NO:610). The BCMA-26 scFv was observed to recognize an epitopecomprising residues present in ₈CSQNEYF₁₄ (set forth in SEQ ID NO:611)and ₁₇LLHACIPCQLR₂₇ (set forth in SEQ ID NO:612). BCMA-52-scFv-mFc wasobserved to bind to an epitope containing residues of the followingdiscontinuous peptides: ₁₀QNEYF₁₄ (SEQ ID NO:613), ₂₁CIPCQL₂₆ (SEQ IDNO:614), and ₇CQRYC₄₁ (SEQ ID NO:615). BCMA-55-scFv-mFc was observed tospecifically bind to an epitope containing residues present in peptidescomprising discontinuous portions of the BCMA polypeptide sequence,individually comprising the following sequences: ₁MLMAG₆ (SEQ IDNO:616), ₁₃YFDSL₁₇ (SEQ ID NO:618), and ₂₅QLRCSSNTPPL₃₅ (SEQ ID NO:619).In some embodiments, the provided antibody or receptor specificallybinds to an epitope comprising residues present within one or more of,e.g., each of discontinuous peptides having the sequences of: MLMAG (SEQID NO:616), YFDSL (SEQ ID NO:618), and QLRCSSNTPPL (SEQ ID NO:619). Insome aspects, the provided antibody or receptor specifically binds to anepitope comprising residues present within one or more of, e.g., eachof, the following discontinuous peptides having the sequences of: MLMAG(SEQ ID NO:616), YFDSLL (SEQ ID NO:620), and QLRCSSNTPPL (SEQ IDNO:619); in some aspects, the provided antibody or receptor specificallybinds to an epitope comprising residues present within one or more of,e.g., each of, the following discontinuous peptides having the sequencesof: MLMAG (SEQ ID NO:617), QNEYFDSLL (SEQ ID NO:617), and QLRCSSNTPPL(SEQ ID NO:619).

The present invention is not intended to be limited in scope to theparticular disclosed embodiments, which are provided, for example, toillustrate various aspects of the invention. Various modifications tothe compositions and methods described will become apparent from thedescription and teachings herein. Such variations may be practicedwithout departing from the true scope and spirit of the disclosure andare intended to fall within the scope of the present disclosure.

SEQUENCES SEQ ID NO SEQUENCE Description   1 DYAMSBCMA-1, -3, -4, -5, -6, -7, -8, -25, -31, -42,  -44, -45, -46, -51 CDR-H1 (aa) Kabat numbering   2 DYYMS BCMA-2, -9, -10, -12, -17, -21, -22, -23, -24,  -26, -32, -33, -35, -36, -37, -38, -40, -41, -47,  -48, -49 CDR-H1 (aa) Kabat numbering   3 DYAMHBCMA-11, -20, -27,  -28, -29, -30, -34, -39 CDR-H1 (aa) Kabat numbering  4 FIRSKAYGGTTEYAASVKG BCMA-1, -3, -4, -5, -6, -7, -8, -25, -31, -42, -44, -45, -46, -51  CDR-H2 (aa) Kabat numbering   5 YISSSGSTIYYADSVKGBCMA-2, -9, -10, -12,  -17, -21, -22, -23, -26, -32, -35, -36, -37, -38,  -40, -47, -48, -49  CDR-H2 (aa) Kabatnumbering   6 GISWNSGSIGYADSVKG BCMA-11, -20, -24, -27, -29, -30, -34, -39 CDR-H2 (aa) Kabat numbering   7 WSAPTDYBCMA-1, -3, -4, -5, -6, -7, -8, -25, -31, -42,  -44, -45, -46, -51 andVH-2 CDR-H3 (aa)   8 VDGPPSSDI BCMA-2 CDR-H3 (aa)   9 VDGDYVDDYBCMA-9, -36, -37, -38, -41 and VH-8 CDR-H3 (aa)  10 VDGPPSFDIBCMA-10, -12, -26,  -32, -47, -48, -49 and VH-1 CDR-H3 (aa)  11DLGPDYDPDAFDI BCMA-11, -34  CDR-H3 (aa)  12 GFTFGDYBCMA-1, -3, -4, -5, -6, -7, -8, -25, -30, -31,  -42, -44, -45, -46, -51CDR-H1 (aa) Chothia numbering  13 GFTFSDY BCMA-2, -9, -12, -17, -21, -22, -23, -24, -26,  -32, -33, -35, -36, -37, -38, -40, -47, -48, -49 CDR-H1 (aa) Chothia numbering  14 GFPFSDYBCMA-10 CDR-H1 (aa) Chothia numbering  15 GFTFDDY BCMA-11, -20, -27, -28, -29, -34, -39  CDR-H1 (aa) Chothia numbering  16 RSKAYGGTBCMA-1, -3, -4, -5, -6, -7, -8, -25, -31, -42,  -44, -45, -46, -51 CDR-H2 (aa) Chothia numbering  17 SSSGST BCMA-2, -9, -10, -12, -17, -21, -22, -23, -26,  -32, -35, -36, -38, -40,  -47, -48 CDR-H2 (aa)Chothia numbering  18 SWNSGS BCMA-11, -20, -24,  -27, -29, -30, -34, -39CDR-H2 (aa) Chothia numbering  19 GFTFGDYAMS BCMA-1, -3, -4, -5, -6,-7, -8, -25, -31, -42,  -44, -45, -46, -51  CDR-H1 (aa) AbM numbering 20 GFTFSDYYMS BCMA-2, -9, -12, -17,  -21, -22, -23, -24, -26, -32, -33, -35, -36, -37,  -38, -40, -47, -48, -49 CDR-H1 (aa) AbMnumbering  21 GFPFSDYYMS BCMA-10 CDR-H1 (aa) AbM numbering  22GFTFDDYAMH BCMA-11, -20, -27,  -28, -29, -34, -39  CDR-H1 (aa) AbMnumbering  23 FIRSKAYGGTTE BCMA-1, -3, -4, -5, -6,-7, -8, -25, -31, -42,  -44, -45, -46, -51  CDR-H2 (aa) AbM numbering 24 YISSSGSTIY BCMA-2, -9, -10, -12,  -17, -21, -22, -23, -26, -32, -35, -36, -38, -40,  -47, -48 CDR-H2 (aa) AbM numbering  25GISWNSGSIG BCMA-11, -20, -24,  -27, -29, -30, -34, -39 CDR-H2 (aa) AbMnumbering  26 KSSQSVLSTSNNKNYLA BCMA-1 CDR-L1 (aa)  27 RASQSIKTNLABCMA-2 CDR-L1 (aa)  28 KSSQSVLHSSNNKNYLA BCMA-3, -46 CDR-L1 (aa)  29RASQDIRNSLA BCMA-4 CDR-L1 (aa)  30 KSSQSVLYSSNNKNYLA BCMA-5, -8, -24 CDR-L1 (aa)  31 RASQSISNSLA BCMA-6 CDR-L1 (aa)  32 RASQDIGDYLABCMA-7 CDR-L1 (aa)  33 GANNIGSKSVH BCMA-9, -26, -35 CDR-L1 (aa)  34GGNNIERKNVH BCMA-10 CDR-L1 (aa)  35 SGSSSNIGSNAVN BCMA-11 CDR-L1 (aa) 36 SGSRSNIGNNYVS BCMA-12 CDR-L1 (aa)  37 WASTREA BCMA-1 CDR-L2 (aa)  38AASTRAT BCMA-2 CDR-L2 (aa)  39 WASTRES BCMA-3, -5, -8, -31, -44, -46 CDR-L2 (aa)  40 AASRLES BCMA-4, -42 CDR-L2 (aa)  41 AASNVEDBCMA-6 CDR-L2 (aa)  42 VASTLQS BCMA-7 CDR-L2 (aa)  43 DDDDRPSBCMA-9, -26, -35 CDR-L2 (aa)  44 DDSDRAS BCMA-10 CDR-L2 (aa)  45 NSHQRPSBCMA-11 CDR-L2 (aa)  46 DNAKRPS BCMA-12 CDR-L2 (aa)  47 QQYFSSPYTBCMA-1 CDR-L3 (aa)  48 QQYGSSPT BCMA-2 CDR-L3 (aa)  49 QQYYTTPLTBCMA-3, -46 CDR-L3 (aa)  50 QQYYSLPLS BCMA-4 CDR-L3 (aa)  51 QQYYSTPWTBCMA-5 CDR-L3 (aa)  52 QQSHMYPPT BCMA-6 CDR-L3 (aa)  53 QQYHSHPWTBCMA-7 CDR-L3 (aa)  54 QQYYSTPYT BCMA-8, -31 CDR-L3 (aa)  55 HVWDRSRDHYVBCMA-9 CDR-L3 (aa)  56 QAWDSSSTLYV BCMA-10 CDR-L3 (aa)  57 AAWDDSLRGYVBCMA-11 CDR-L3 (aa)  58 QVWDSSSDHWV BCMA-12, -32, -48 CDR-L3 (aa)  59QVQLVQSGGGLVQPGRSLRLSCTASGFTFG BCMA-1, -3, -4, -5, -6,-7, -8, -45, -46 VH FR1 (aa)  60 EVQLVESGGGLVKPGGSLRLSCAASGFTFSBCMA-2, -12, -22, -23, -26, -40, -48 VH FR1 (aa)  61EVQLVQSGGGLVKPGGSLRLSCAASGFTFS BCMA-9, -24, -35, -37 VH FR1 (aa)  62EVQLVESGGGLVKPGGSLRLSCAASGFPFS BCMA-10 VH FR1 (aa)  63QVQLVQSGGGLVQPGRSLRLSCAASGFTFD BCMA-11, -28, -29,  -39 VH FR1 (aa)  64WFRQAPGKGLEWVG BCMA-1, -3, -4, -5, -6, -7, -8, -25, -31, -42, -44, -45, -46, -51 VH FR2 (aa)  65 WIRQAPGKGLEWVS BCMA-2, -9, -10, -12, -21, -22, -23, -24, -26,  -32, -33, -35, -36, -37, -38, -40, -41, -47, -48,  -49 VH FR2 (aa)  66 WVRRAPGKGLEWVSBCMA-11 VH FR2 (aa)  67 RFTISRDDSKSIAYLQMNSLKTEDTAVYYCAABCMA-1, -3, -4, -5, -6, -7, -8, -25, -31, -42,  -44, -45, -46, -51 VHFR3 (aa)  68 RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAK BCMA-2, -10, - 12, -21,-22, -23, -26, -32, -40,  -41, -48, -49 VH FR3 (aa)  69RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR BCMA-9, -11, -17, -24,-28, -29, -30, -33, -34,  -35, -36, -38, -39 VH FR3 (aa)  70 WGQGTLVTVSSBCMA-1, -3, -4, -5, -6, -7, -8, -9, -15, -16, -18,-20, -21, -22, -23, -25,  -27, -31, -35, -36, -37, -38, -40, -41, -42, -44,  -45, -46, -51 VH FR4 (aa)  71 WGQGTMVTVSSBCMA-2, -10, -11, -12, -24, -26, -29, -30, -32,  -34, -39, -48, -49, -50VH FR4 (aa)  72 DIVMTQSPDSLSVSPGERATISC BCMA-1 VL FR1 (aa)  73EIVMTQSPATLSVSPGETATLSC BCMA-2 VL FR1 (aa)  74 DIVMTQSPDSLVVSLGERATINCBCMA-3, -46 VL FR1 (aa)  75 AIRMTQSPSSLSASLGDRVTITC BCMA-4 VL FR1 (aa) 76 DIVMTQSPDSLAVSLGERATINC BCMA-5, -8, -24 VL FR1 (aa)  77DIVMTQSPSSLSVSVGERVTITC BCMA-6 VL FR1 (aa)  78 VIQLTQSPSSLSASVGDRVTITCBCMA-7 VL FR1 (aa)  79 SYELTOPPSVSVAPGQTARVTC BCMA-9 VL FR1 (aa)  80SYVLTQPPSVSVAPGQTARITC BCMA-10, -26 VL FR1 (aa)  81QLVLTQPPSASGTPGQRVTISC BCMA-11 VL FR1 (aa)  82 QSALTQPPSVSAAPGQKVTISCBCMA-12 VL FR1 (aa)  83 WYQQKPGQPPRLLLY BCMA-1 VL FR2 (aa)  84WYQQKPGQAPRLLIY BCMA-2, -34 VL FR2 (aa)  85 WYQQKPGQPPKLLIYBCMA-3, -5, -8, -24,  -44, -46 VL FR2 (aa)  86 WYQQRPGKAPKLLLSBCMA-4 VL FR2 (aa)  87 WYKQRPGEAPKLLIH BCMA-6 VL FR2 (aa)  88WFQQRPGKAPKSLIY BCMA-7 VL FR2 (aa)  89 WYQQKPGQAPMLVVYBCMA-9, -26, -35 VL FR2 (aa)  90 WYQQKPGQAPVPVVY BCMA-10 VL FR2 (aa)  91WYQQLPGTAPEVLIY BCMA-11 VL FR2 (aa)  92 WYQQLPGTAPKLLIYBCMA-12 VL FR2 (aa)  93 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCBCMA-1, -3, -5, -8,  -31, -44, -46 VL FR3 (aa)  94GIPDRFSGSGSGTDFTLTITRLEPEDFAVYYC BCMA-2 VL FR3 (aa)  95GVPSRFSGTTSGAEYALSISSLOPEDVASYFC BCMA-4 VL FR3 (aa)  96GVPSRFSGRGSGTVFTLAISNVQPEDFATYYC BCMA-6 VL FR3 (aa)  97GVPSRFSGSGSGTHFTLTINSLQPEDFATYYC BCMA-7 VL FR3 (aa)  98GIPERFSGSNSGNTATLTISGVEAGDEADYFC BCMA-9, -26, -35 VL FR3 (aa)  99GIPERFSASNSGNTATLTISGAQATDEAEYYC BCMA-10 VL FR3 (aa) 100GVPDRFSGSKSGTSASLAINGLQSEDEADYYC BCMA-11 VL FR3 (aa) 101GIPDRFSGSKSGTSATLDIAGLQTGDEADYYC BCMA-12 VL FR3 (aa) 102 FGHGTKLEIKBCMA-1 VL FR4 (aa) 103 FGRGTKLEIK BCMA-2, -39 VL FR4 (aa) 104 FGGGTKVEIKBCMA-3, -4, -6, -30,  -46 VL FR4 (aa) 105 FGQGTKVDIK BCMA-5, -45 VL FR4(aa) 106 FGPGTKVDIK BCMA-7 VL FR4 (aa) 107 FGQGTKLEIK BCMA-8, -44 VL FR4(aa) 108 FGTGTKLTVL BCMA-9, -10, -11, -26, -40, -47 VL FR4 (aa) 109FGGGTKLTVL BCMA-12, -14, -15,  -16, -17, -18, -32, -33, -36, -37, -38, -41, -48,  -49, -50 VL FR4 (aa) 110QVQLVQSGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGTBCMA-1, -3, -4, -5, -6,TEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSS-7, -8, -45, -46 VH Chain (aa) 111EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-2 V_(H) Chain (aa)YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGPPSSDIWGQGTMVTVSS 112EVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-9 V_(H) Chain (aa)YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARVDGDYVDDYWGQGTLVTVSS 113EVQLVESGGGLVKPGGSLRLSCAASGFPFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-10 V_(H) ChainYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGPPSFDIWGQGTMVTVSS (aa) 114QVQLVQSGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRRAPGKGLEWVSGISWNSGSIGBCMA-11 V_(H) ChainYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLGPDYDPDAFDIWGQGTMV (aa) TVSS115 EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-12, -26, -48 V_(H)YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGPPSFDIWGQGTMVTVSS Chain (aa)116 DIVMTQSPDSLSVSPGERATISCKSSQSVLSTSNNKNYLAWYQQKPGQPPRLLLYWASTBCMA-1 V_(L) Chain (aa)REAGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYFSSPYTFGHGTKLEIK 117EIVMTQSPATLSVSPGETATLSCRASQSIKTNLAWYQQKPGQAPRLLIYAASTRATGIPBCMA-2 V_(L) Chain (aa) DRFSGSGSGTDFTLTITRLEPEDFAVYYCQQYGSSPTFGRGTKLEIK118 DIVMTQSPDSLVVSLGERATINCKSSQSVLHSSNNKNYLAWYQQKPGQPPKLLIYWASTBCMA-3, -46 VL RESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYTTPLTFGGGTKVEIKChain (aa) 119AIRMTQSPSSLSASLGDRVTITCRASQDIRNSLAWYQQRPGKAPKLLLSAASRLESGVPBCMA-4 V_(L) Chain (aa) SRFSGTTSGAEYALSISSLQPEDVASYFCQQYYSLPLSFGGGTKVEIK120 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTBCMA-5 V_(L) Chain (aa)RESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPWTFGQGTKVDIK 121DIVMTQSPSSLSVSVGERVTITCRASQSISNSLAWYKQRPGEAPKLLIHAASNVEDGVPBCMA-6 V_(L) Chain (aa) SRFSGRGSGTVFTLAISNVQPEDFATYYCQQSHMYPPTFGGGTKVEIK122 VIQLTQSPSSLSASVGDRVTITCRASQDIGDYLAWFQQRPGKAPKSLIYVASTLQSGVPBCMA-7 V_(L) Chain (aa) SRFSGSGSGTHFTLTINSLQPEDFATYYCQQYHSHPWTFGPGTKVDIK123 DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTBCMA-8 V_(L) Chain (aa)RESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPYTFGQGTKLEIK 124SYELTQPPSVSVAPGQTARVTCGANNIGSKSVHWYQQKPGQAPMLVVYDDDDRPSGIPEBCMA-9 V_(L) Chain (aa)RFSGSNSGNTATLTISGVEAGDEADYFCHVWDRSRDHYVFGTGTKLTVL 125SYVLTQPPSVSVAPGQTARITCGGNNIERKNVHWYQQKPGQAPVPVVYDDSDRASGIPEBCMA-10 V_(L) Chain RFSASNSGNTATLTISGAQATDEAEYYCQAWDSSSTLYVFGTGTKLTVL(aa) 126 QLVLTQPPSASGTPGQRVTISCSGSSSNIGSNAVNWYQQLPGTAPEVLIYNSHQRPSGVBCMA-11 V_(L) Chain PDRFSGSKSGTSASLAINGLQSEDEADYYCAAWDDSLRGYVFGTGTKLTVL(aa) 127 QSALTQPPSVSAAPGQKVTISCSGSRSNIGNNYVSWYQQLPGTAPKLLIYDNAKRPSGIBCMA-12 V_(L) Chain PDRFSGSKSGTSATLDIAGLQTGDEADYYCQVWDSSSDHWVFGGGTKLTVL(aa) 128 QVQLVQSGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGTBCMA-1 scFv (aa)TEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLSVSPGERATISCKSSQSVLSTSNNKNYLAWYQQKPGQPPRLLLYWASTREAGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYFSSPYT FGHGTKLEIK129 EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-2 scFv (aa)YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGPPSSDIWGQGTMVTVSSGGGGSGGGGSGGGGSEIVMTQSPATLSVSPGETATLSCRASQSIKTNLAWYQQKPGQAPRLLIYAASTRATGIPDRFSGSGSGTDFTLTITRLEPEDFAVYYCQQYGSSPTFGRGTKL EIK 130QVQLVQSGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGTBCMA-3, 46 scFv (aa)TEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLVVSLGERATINCKSSQSVLHSSNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYTTPLT FGGGTKVEIK131 QVQLVQSGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGTBCMA-4 scFv (aa)TEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSSGGGGSGGGGSGGGGSAIRMTQSPSSLSASLGDRVTITCRASQDIRNSLAWYQQRPGKAPKLLLSAASRLESGVPSRFSGTTSGAEYALSISSLQPEDVASYFCQQYYSLPLSFGGGTK VEIK 132QVQLVQSGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGTBCMA-5 scFv (aa)TEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPWT FGQGTKVDIK133 QVQLVQSGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGTBCMA-6 scFv (aa)TEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPSSLSVSVGERVTITCRASQSISNSLAWYKQRPGEAPKLLIHAASNVEDGVPSRFSGRGSGTVFTLAISNVQPEDFATYYCQQSHMYPPTFGGGTK VEIK 134QVQLVQSGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGTBCMA-7 scFv (aa)TEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSSGGGGSGGGGSGGGGSVIQLTQSPSSLSASVGDRVTITCRASQDIGDYLAWFQQRPGKAPKSLIYVASTLQSGVPSRFSGSGSGTHFTLTINSLQPEDFATYYCQQYHSHPWTFGPGTK VDIK 135QVQLVQSGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGTBCMA-8 scFv (aa)TEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPYT FGQGTKLEIK136 EVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-9 scFv (aa)YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARVDGDYVDDYWGQGTLVTVSSGGGGSGGGGSGGGGSSYELTQPPSVSVAPGQTARVTCGANNIGSKSVHWYQQKPGQAPMLVVYDDDDRPSGIPERFSGSNSGNTATLTISGVEAGDEADYFCHVWDRSRDHYVFGTGT KLTVL 137EVQLVESGGGLVKPGGSLRLSCAASGFPFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-10 scFv (aa)YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGPPSFDIWGQGTMVTVSSGGGGSGGGGSGGGGSSYVLTQPPSVSVAPGQTARITCGGNNIERKNVHWYQQKPGQAPVPVVYDDSDRASGIPERFSASNSGNTATLTISGAQATDEAEYYCQAWDSSSTLYVFGTGT KLTVL 138QVQLVQSGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRRAPGKGLEWVSGISWNSGSIGBCMA-11 scFv (aa)YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLGPDYDPDAFDIWGQGTMVTVSSGGGGSGGGGSGGGGSQLVLTQPPSASGTPGQRVTISCSGSSSNIGSNAVNWYQQLPGTAPEVLIYNSHQRPSGVPDRFSGSKSGTSASLAINGLQSEDEADYYCAAWDDSLRGY VFGTGTKLTVL139 EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-12 scFv (aa)YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGPPSFDIWGQGTMVTVSSGGGGSGGGGSGGGGSQSALTQPPSVSAAPGQKVTISCSGSRSNIGNNYVSWYQQLPGTAPKLLIYDNAKRPSGIPDRFSGSKSGTSATLDIAGLQTGDEADYYCQVWDSSSDHWVFGG GTKLTVL 140SYAMH BCMA-13 CDR-H1 (aa) Kabat numbering 141 SYGMH BCMA-14, -15 CDR-H1 (aa) Kabat numbering 142 SSAMQ BCMA-16 CDR-H1(aa) Kabat numbering 143 SYWMS BCMA-18 CDR-H1 (aa) Kabat numbering 144SYYMH BCMA-19 CDR-H1 (aa) Kabat numbering 145 VISYDGSNKYYADSVKGBCMA-13, -14, -15 CDR-H2 (aa) Kabat numbering 146 WIVVGSGNTNYAQKFQEBCMA-16 CDR-H2 (aa) Kabat numbering 147 HINQDGSEKYYVDSVKG BCMA-18 CDR-H2(aa) Kabat numbering 148 WINPNSGGTNYAQKFQG BCMA-19 CDR-H2(aa) Kabat numbering 149 LPGRDGYPGAFDY BCMA-13, -14  CDR-H3 (aa) 150DQYSSSAQRADFDY BCMA-15 CDR-H3 (aa) 151 APYYDILTGYYL BCMA-16 CDR-H3 (aa)152 EADSSADY BCMA-17, -33  CDR-H3 (aa) 153 WLAVTN BCMA-18 CDR-H3 (aa)154 DGGDV BCMA-19 CDR-H3 (aa) 155 GGLGITPYYFDY BCMA-20, -27  CDR-H3 (aa)156 VDGGYTEDY BCMA-21 CDR-H3 (aa) 157 VDGDYTEDY BCMA-22, -23, -40CDR-H3 (aa) 158 GFTFSSY BCMA-13, -14, -15,  -18 CDR-H1 (aa)Chothia numbering 159 GFTFTSS BCMA-16 CDR-H1 (aa) Chothia numbering 160GYTFTSY BCMA-19 CDR-H1 (aa) Chothia numbering 161 SYDGSNBCMA-13, -14, -15 CDR-H2 (aa) Chothia numbering 162 VVGSGNBCMA-16 CDR-H2 (aa) Chothia numbering 163 NQDGSE BCMA-18 CDR-H2(aa) Chothia numbering 164 NPNSGG BCMA-19 CDR-H2 (aa) Chothia numbering165 GFTFSSYAMH BCMA-13 CDR-H1 (aa) AbM numbering 166 GFTFSSYGMHBCMA-14, -15  CDR-H1 (aa) AbM numbering 167 GFTFTSSAMQ BCMA-16 CDR-H1(aa) AbM numbering 168 GFTFSSYWMS BCMA-18 CDR-H1 (aa) AbM numbering 169GYTFTSYYMH BCMA-19 CDR-H1 (aa) AbM numbering 170 VISYDGSNKYBCMA-13, -14, -15 CDR-H2 (aa) AbM numbering 171 WIVVGSGNTNBCMA-16 CDR-H2 (aa) AbM numbering 172 HINQDGSEKY BCMA-18 CDR-H2(aa) AbM numbering 173 WINPNSGGTN BCMA-19 CDR-H2 (aa) AbM numbering 174GSGSNIGSNDVS BCMA-13, -14, -15,  -16, -18, -21 CDR-L1 (aa) 175GGNNIGFKGVQ BCMA-17, -33  CDR-L1 (aa) 176 TGTSSDVGDYNYVA BCMA-19 CDR-L1(aa) 177 SGGKTVN BCMA-20, -27  CDR-L1 (aa) 178 TGSSSDVGKYNLVSBCMA-22, -23  CDR-L1 (aa) 179 WNDQRPS BCMA-13, -14, -15, -16, -18, -21 CDR-L2 (aa) 180 DDSDRPS BCMA-17, -32, -33 CDR-L2 (aa) 181EVINRPS BCMA-19 CDR-L2 (aa) 182 SNDQRPS BCMA-20, -27  CDR-L2 (aa) 183DVNKRPS BCMA-22, -23, -40 CDR-L2 (aa) 184 AAWDDSLGGSWV BCMA-13 CDR-L3(aa) 185 AAWDDRLNGFWV BCMA-14 CDR-L3 (aa) 186 AAWDDSLSGWV BCMA-15 CDR-L3(aa) 187 ASWDDSLSGWV BCMA-16 CDR-L3 (aa) 188 QVWDSASDHWV BCMA-17, -33 CDR-L3 (aa) 189 AAWDDSLNGWV BCMA-18 CDR-L3 (aa) 190 ISYSRGSTPYVBCMA-19 CDR-L3 (aa) 191 GSWDDSLNAWV BCMA-20, -27  CDR-L3 (aa) 192AAWDDSLNGYV BCMA-21 CDR-L3 (aa) 193 CSYGGSRSYV BCMA-22, -40  CDR-L3 (aa)194 SSYGGSRSYV BCMA-23 CDR-L3 (aa) 195 QMQLVQYGGGVVQPGRSLRLSCAASGFTFSBCMA-13 VH FR1 (aa) 196 EVQLLESGGGVVQPGRSLRLSCAASGFTFS BCMA-14 VH FR1(aa) 197 QVQLLESGGGLVKPGGSLRLSCAASGFTFS BCMA-15, -47 VH FR1 (aa) 198EVQLVQSGPEVKKPGTSVKVSCKASGFTFT BCMA-16 VH FR1 (aa) 199QVQLVQSGGGLVKPGGSLRLSCAASGFTFS BCMA-17, -33, -36,  -38, -41 VH FR1 (aa)200 EVQLLESGGGLVQPGGSLRLSCAASGFTFS BCMA-18 VH FR1 (aa) 201QVQLVQSGAEVKKPGASVKVSCKASGYTFT BCMA-19 VH FR1 (aa) 202EVQLLESGGGLVQPGRSLRLSCAASGFTFD BCMA-20 VH FR1 (aa) 203EVQLVESGGGLVKPGGSLKLSCAASGFTFS BCMA-21 VH FR1 (aa) 204 WVRQAPGKGLEWVABCMA-13, -14, -15 VH FR2 (aa) 205 WVRQARGQRLEWIG BCMA-16 VH FR2 (aa) 206WIRLAPGKGLEWVS BCMA-17 VH FR2 (aa) 207 WHRQAPGKGPEWVA BCMA-18 VH FR2(aa) 208 WVRQAPGQGLEWMG BCMA-19 VH FR2 (aa) 209 WVRQAPGKGLEWVSBCMA-20, -27, -28,  -29, -30, -34, -39 VH FR2 (aa) 210RFTISRDNSKNTLYLQMNSLKAEDTAVYYCAT BCMA-13 VH FR3 (aa) 211RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAT BCMA-14 VH FR3 (aa) 212RFTISRDNSKNTLYLQMNSLRAEDTAVYYCAK BCMA-15 VH FR3 (aa) 213RVTITRDMSTSTAYMELSSLRSEDTAVYYCAA BCMA-16 VH FR3 (aa) 214RFTISRDNAESSLYLQMNSLRAEDTAVYYCAR BCMA-18 VH FR3 (aa) 215RVTMTRDTSISTAYMELSRLRSDDTAVYYCAR BCMA-19 VH FR3 (aa) 216RFTISRDNAKNSLYLQMNSLRAEDTALYYCAK BCMA-20, -27 VH FR3 (aa) 217RGQGTLVTVSS BCMA-13 VH FR4 (aa) 218 RGPGTLVTVSS BCMA-14 VH FR4 (aa) 219WGQGTLVNVSS BCMA-17, -33 VH FR4 (aa) 220 WGQGTTVTVSS BCMA-19 VH FR4 (aa)221 QAVLTQPPSASGTPGQRVTISC BCMA-13, -14 VL FR1 (aa) 222QSVLTQPPSASGTPGQRVTISC BCMA-15, -18, -21 VL FR1 (aa) 223QSALTQPPSASGTPGQRVTISC BCMA-16 VL FR1 (aa) 224 QPVLTQPPSVSVAPGKTAMITCBCMA-17, -33 VL FR1 (aa) 225 QAVLTQPASVSGSPGQSITISC BCMA-19 VL FR1 (aa)226 QPVLTQPPSASGTPGQRVTISC BCMA-20, -27 VL FR1 (aa) 227QSALTQPASVSGSPGQSITISC BCMA-22, -23, -40 VL FR1 (aa) 228 WYQQIPGTAPKLLIYBCMA-13, -14, -15,  -16, -18, -21 VL FR2 (aa) 229 WYQQKTGQAPVLVVYBCMA-17, -33 VL FR2 (aa) 230 WYQQHPGKDPKLMIF BCMA-19 VL FR2 (aa) 231WFRQVPGTAPQLLIY BCMA-20, -27 VL FR2 (aa) 232 WYQQPPGKAPKLIIYBCMA-22, -23, -40 VL FR2 (aa) 233 GVPDRFSASKSGTSASLAISGLRSEDEADYYCBCMA-13 VL FR3 (aa) 234 GVPDRFSGSKSGASASLAISGLQSEDEADYYCBCMA-14 VL FR3 (aa) 235 GVPDRFSGSKSGTSASLVISGLRSEDEADYYCBCMA-15 VL FR3 (aa) 236 GVPDRFSGSKSGTSASLAISGLQSEDEADYYCBCMA-16 VL FR3 (aa) 237 GIPERFSGSNSGNTATLTISRVEAGDEADYYCBCMA-17, -33 VL FR3 (aa) 238 GVPDRFSGSKSGTSASLAISGLRSEDEADYYCBCMA-18 VL FR3 (aa) 239 GVSDRFSGSKSGNTASLDISGLQPEDEADYYCBCMA-19 VL FR3 (aa) 240 GVPDRFSGSKSGSSASLDISGLQSEDEAYYYCBCMA-20, -27 VL FR3 (aa) 241 GVPDRFSGSKSGISASLAISGLRSEDEADYYCBCMA-21 VL FR3 (aa) 242 GVSNRFSGSKSGNTATLTISGLQGDDEADYYCBCMA-22, -23, -40 VL FR3 (aa) 243 FGGGTKVTVL BCMA-13 VL FR4 (aa) 244IGTGTKVTVL BCMA-19 VL FR4 (aa) 245 FGGETKLTVL BCMA-20, -27 VL FR4 (aa)246 FGTGTKVTVL BCMA-21, -22, -23 VL FR4 (aa) 247QMQLVQYGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISYDGSNKYBCMA-13 V_(H) ChainYADSVKGRFTISRDNSKNTLYLQMNSLKAEDTAVYYCATLPGRDGYPGAFDYRGQGTLV (aa) TVSS248 EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYBCMA-14 V_(H) ChainYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATLPGRDGYPGAFDYRGPGTLV (aa) TVSS249 QVQLLESGGGLVKPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYBCMA-15 V_(H) ChainYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDQYSSSAQRADFDYWGQGTL (aa) VTVSS250 EVQLVQSGPEVKKPGTSVKVSCKASGFTFTSSAMQWVRQARGQRLEWIGWIVVGSGNTNBCMA-16 V_(H) ChainYAQKFQERVTITRDMSTSTAYMELSSLRSEDTAVYYCAAAPYYDILTGYYLWGQGTLVT (aa) VSS 251QVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRLAPGKGLEWVSYISSSGSTIYBCMA-17 V_(H) ChainYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREADSSADYWGQGTLVNVSS (aa) 252EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYWMSWHRQAPGKGPEWVAHINQDGSEKYBCMA-18 V_(H) ChainYVDSVKGRFTISRDNAESSLYLQMNSLRAEDTAVYYCARWLAVTNWGQGTLVTVSS (aa) 253QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGWINPNSGGTNBCMA-19 V_(H) ChainYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDGGDVWGQGTTVTVSS (aa) 254EVQLLESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIGBCMA-20 V_(H) ChainYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKGGLGITPYYFDYWGQGTLVT (aa) VSS 255EVQLVESGGGLVKPGGSLKLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-21 V_(H) ChainYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGGYTEDYWGQGTLVTVSS (aa) 256EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-22, -23, -40 V_(H)YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGDYTEDYWGQGTLVTVSS Chain (aa)257 QAVLTQPPSASGTPGQRVTISCSGSGSNIGSNDVSWYQQIPGTAPKLLIYWNDQRPSGVBCMA-13 V_(L) Chain PDRFSASKSGTSASLAISGLRSEDEADYYCAAWDDSLGGSWVFGGGTKVTVL(aa) 258 QAVLTQPPSASGTPGQRVTISCSGSGSNIGSNDVSWYQQIPGTAPKLLIYWNDQRPSGVBCMA-14 V_(L) Chain PDRFSGSKSGASASLAISGLQSEDEADYYCAAWDDRLNGFWVFGGGTKLTVL(aa) 259 QSVLTQPPSASGTPGQRVTISCSGSGSNIGSNDVSWYQQIPGTAPKLLIYWNDQRPSGVBCMA-15 V_(L) Chain PDRFSGSKSGTSASLVISGLRSEDEADYYCAAWDDSLSGWVFGGGTKLTVL(aa) 260 QSALTQPPSASGTPGQRVTISCSGSGSNIGSNDVSWYQQIPGTAPKLLIYWNDQRPSGVBCMA-16 V_(L) Chain PDRFSGSKSGTSASLAISGLQSEDEADYYCASWDDSLSGWVFGGGTKLTVL(aa) 261 QPVLTQPPSVSVAPGKTAMITCGGNNIGFKGVQWYQQKTGQAPVLVVYDDSDRPSGIPEBCMA-17, -33 V_(L) RFSGSNSGNTATLTISRVEAGDEADYYCQVWDSASDHWVFGGGTKLTVLChain (aa) 262QSVLTQPPSASGTPGQRVTISCSGSGSNIGSNDVSWYQQIPGTAPKLLIYWNDQRPSGVBCMA-18 V_(L) Chain PDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGWVFGGGTKLTVL(aa) 263 QAVLTQPASVSGSPGQSITISCTGTSSDVGDYNYVAWYQQHPGKDPKLMIFEVINRPSGBCMA-19 V_(L) Chain VSDRFSGSKSGNTASLDISGLQPEDEADYYCISYSRGSTPYVIGTGTKVTVL(aa) 264 QPVLTQPPSASGTPGQRVTISCSGGKTVNWFRQVPGTAPQLLIYSNDQRPSGVPDRFSGBCMA-20, -27 V_(L) SKSGSSASLDISGLQSEDEAYYYCGSWDDSLNAWVFGGETKLTVLChain (aa) 265QSVLTQPPSASGTPGQRVTISCSGSGSNIGSNDVSWYQQIPGTAPKLLIYWNDQRPSGVBCMA-21 V_(L) Chain PDRFSGSKSGISASLAISGLRSEDEADYYCAAWDDSLNGYVFGTGTKVTVL(aa) 266 QSALTQPASVSGSPGQSITISCTGSSSDVGKYNLVSWYQQPPGKAPKLITYDVNKRPSGBCMA-22 V_(L) Chain VSNRFSGSKSGNTATLTISGLQGDDEADYYCCSYGGSRSYVFGTGTKVTVL(aa) 267 QSALTQPASVSGSPGQSITISCTGSSSDVGKYNLVSWYQQPPGKAPKLIIYDVNKRPSGBCMA-23 V_(L) Chain VSNRFSGSKSGNTATLTISGLQGDDEADYYCSSYGGSRSYVFGTGTKVTVL(aa) 268 QMQLVQYGGGVVQPGRSLRLSCAASGFTFSSYAMHWVRQAPGKGLEWVAVISYDGSNKYBCMA-13 scFv (aa)YADSVKGRFTISRDNSKNTLYLQMNSLKAEDTAVYYCATLPGRDGYPGAFDYRGQGTLVTVSSGGGGSGGGGSGGGGSQAVLTQPPSASGTPGQRVTISCSGSGSNIGSNDVSWYQQIPGTAPKLLIYWNDQRPSGVPDRFSASKSGTSASLAISGLRSEDEADYYCAAWDDSLGGS WVFGGGTKVTVL269 EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYBCMA-14 scFv (aa)YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATLPGRDGYPGAFDYRGPGTLVTVSSGGGGSGGGGSGGGGSQAVLTQPPSASGTPGQRVTISCSGSGSNIGSNDVSWYQQIPGTAPKLLIYWNDQRPSGVPDRFSGSKSGASASLAISGLQSEDEADYYCAAWDDRLNGF WVFGGGTKLTVL270 QVQLLESGGGLVKPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYBCMA-15 scFv (aa)YADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDQYSSSAQRADFDYWGQGTLVTVSSGGGGSGGGGSGGGGSQSVLTQPPSASGTPGQRVTISCSGSGSNIGSNDVSWYQQIPGTAPKLLIYWNDQRPSGVPDRFSGSKSGTSASLVISGLRSEDEADYYCAAWDDSLSG WVFGGGTKLTVL271 EVQLVQSGPEVKKPGTSVKVSCKASGFTFTSSAMQWVRQARGQRLEWIGWIVVGSGNTNBCMA-16 scFv (aa)YAQKFQERVTITRDMSTSTAYMELSSLRSEDTAVYYCAAAPYYDILTGYYLWGQGTLVTVSSGGGGSGGGGSGGGGSQSALTQPPSASGTPGQRVTISCSGSGSNIGSNDVSWYQQIPGTAPKLLIYWNDQRPSGVPDRFSGSKSGTSASLAISGLQSEDEADYYCASWDDSLSGWV FGGGTKLTVL272 QVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRLAPGKGLEWVSYISSSGSTIYBCMA-17 scFv (aa)YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREADSSADYWGQGTLVNVSSGGGGSGGGGSGGGGSQPVLTQPPSVSVAPGKTAMITCGGNNIGFKGVQWYQQKTGQAPVLVVYDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSASDHWVFGGGTK LTVL 273EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYWMSWHRQAPGKGPEWVAHINQDGSEKYBCMA-18 scFv (aa)YVDSVKGRFTISRDNAESSLYLQMNSLRAEDTAVYYCARWLAVTNWGQGTLVTVSSGGGGSGGGGSGGGGSQSVLTQPPSASGTPGQRVTISCSGSGSNIGSNDVSWYQQIPGTAPKLLIYWNDQRPSGVPDRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLNGWVFGGGTK LTVL 274QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGWINPNSGGTNBCMA-19 scFv (aa)YAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDGGDVWGQGTTVTVSSGGGGSGGGGSGGGGSQAVLTQPASVSGSPGQSITISCTGTSSDVGDYNYVAWYQQHPGKDPKLMIFEVINRPSGVSDRFSGSKSGNTASLDISGLQPEDEADYYCISYSRGSTPYVIGTGTK VTVL 275EVQLLESGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIGBCMA-20 scFv (aa)YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKGGLGITPYYFDYWGQGTLVTVSSGGGGSGGGGSGGGGSQPVLTQPPSASGTPGQRVTISCSGGKTVNWFRQVPGTAPQLLIYSNDQRPSGVPDRFSGSKSGSSASLDISGLQSEDEAYYYCGSWDDSLNAWVFGGETK LTVL 276EVQLVESGGGLVKPGGSLKLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-21 scFv (aa)YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGGYTEDYWGQGTLVTVSSGGGGSGGGGSGGGGSQSVLTQPPSASGTPGQRVTISCSGSGSNIGSNDVSWYQQIPGTAPKLLIYWNDQRPSGVPDRFSGSKSGISASLAISGLRSEDEADYYCAAWDDSLNGYVFGT GTKVTVL 277EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-22 scFv (aa)YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGDYTEDYWGQGTLVTVSSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGSSSDVGKYNLVSWYQQPPGKAPKLIIYDVNKRPSGVSNRFSGSKSGNTATLTISGLQGDDEADYYCCSYGGSRSYVFGT GTKVTVL 278EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-23 scFv (aa)YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGDYTEDYWGQGTLVTVSSGGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGSSSDVGKYNLVSWYQQPPGKAPKLITYDVNKRPSGVSNRFSGSKSGNTATLTISGLQGDDEADYYCSSYGGSRSYVFGT GTKVTVL 279VDGDDAFDI V_(H)-3 CDR-H3 (aa) 280 DPLSWDSSGKGPR V_(H)-4 CDR-H3 (aa) 281ENYDFWSWRYYYDMDV V_(H)-5 CDR-H3 (aa) 282 VDGPPSYDI V_(H)-6 CDR-H3 (aa)283 GDWDDAFDI V_(H)-7 CDR-H3 (aa) 284 VDGDYEDY V_(H)-9 CDR-H3 (aa) 285DVPSSGDDAFDI V_(H)-10 CDR-H3 (aa) 286 VDGDDVFDI V_(H)-11 CDR-H3 (aa) 287VDGDAFDI V_(H)-12 CDR-H3 (aa) 288 DYSIN Reference Antibody 1V_(H) CDR-H1 (aa) 289 NFGMN Reference Antibody 2 V_(H) CDR-H1 (aa) 290WINTETREPAYAYDFRG Reference Antibody 1 V_(H) CDR-H2 (aa) 291WINTYTGESYFADDFKG Reference Antibody 2 V_(H) CDR-H2 (aa) 292 DYSYAMDYReference Antibody 1 V_(H) CDR-H3 (aa) 293 GEIYYGYDGGFAYReference Antibody 2 V_(H) CDR-H3 (aa) 294 GYTFTDY Reference Antibody 1V_(H) CDR-H1 (aa) Chothia numbering 295 GYTFTNF Reference Antibody 2V_(H) CDR-H1 (aa) Chothia numbering 296 NTETRE Reference Antibody 1V_(H) CDR-H2 (aa) Chothia numbering 297 NTYTGE Reference Antibody 2V_(H) CDR-H2 (aa) Chothia numbering 298 GYTFTDYSIN Reference Antibody 1V_(H) CDR-H1 (aa) AbM numbering 299 GYTFTNFGMN Reference Antibody 2V_(H) CDR-H1 (aa) AbM numbering 300 WINTETREPA Reference Antibody 1V_(H) CDR-H2 (aa) AbM numbering 301 WINTYTGESY Reference Antibody 2V_(H) CDR-H2 (aa) AbM numbering 302 RASESVTILGSHLIH Reference Antibody 1VL CDR-L1 (aa) 303 RASQDVNTAVS Reference Antibody 2 VL CDR-L1 (aa) 304LASNVQT Reference Antibody 1 VL CDR-L2 (aa) 305 SASYRYTReference Antibody 2 VL CDR-L2 (aa) 306 LQSRTIPRT Reference Antibody 1VL CDR-L3 (aa) 307 QQHYSTPWT Reference Antibody 2 VL CDR-L3 (aa) 308QIQLVQSGPELKKPGETVKISCKASGYTFT Reference Antibody 1 V_(H) FR1 (aa) 309QIQLVQSGPDLKKPGETVKLSCKASGYTFT Reference Antibody 2 V_(H) FR1 (aa) 310WVKRAPGKGLKWMG Reference Antibody 1 V_(H) FR2 (aa) 311 WVKQAPGKGFKWMAReference Antibody 2 V_(H) FR2 (aa) 312 RFAFSLETSASTAYLQINNLKYEDTATYFCALReference Antibody 1 V_(H) FR3 (aa) 313 RFAFSVETSATTAYLQINNLKTEDTATYFCARReference Antibody 2 V_(H) FR3 (aa) 314 WGQGTSVTVSS Reference Antibody 1V_(H) FR4 (aa) 315 WGQGTLVTVSA Reference Antibody 2 V_(H) FR4 (aa) 316DIVLTQSPPSLAMSLGKRATISC Reference Antibody 1 V_(L) FR1 (aa) 317DVVMTQSHRFMSTSVGDRVSITC Reference Antibody 2 V_(L) FR1 (aa) 318WYQQKPGQPPTLLIQ Reference Antibody 1 V_(L) FR2 (aa) 319 WYQQKPGQSPKLLIFReference Antibody 2 V_(L) FR2 (aa) 320 GVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCReference Antibody 1 V_(L) FR3 (aa) 321 GVPDRFTGSGSGADFTLTISSVQAEDLAVYYCReference Antibody 2 V_(L) FR3 (aa) 322 FGGGTKLEIK Reference Antibody 1V_(L) FR4 (aa) 323 FGGGTKLDIK Reference Antibody 2 V_(L) FR4 (aa) 324QIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLKWMGWINTETREPAReference Antibody 1YAYDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDYSYAMDYWGQGTSVTVSSV_(H )Chain (aa) 325QIQLVQSGPDLKKPGETVKLSCKASGYTFTNFGMNWVKQAPGKGFKWMAWINTYTGESYReference Antibody 2FADDFKGRFAFSVETSATTAYLQINNLKTEDTATYFCARGEIYYGYDGGFAYWGQGTLVV_(H) Chain (aa) TVSA 326DIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIHWYQQKPGQPPTLLIQLASNVQReference Antibody 1TGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPRTFGGGTKLEIK V_(L) Chain (aa)327 DVVMTQSHRFMSTSVGDRVSITCRASQDVNTAVSWYQQKPGQSPKLLIFSASYRYTGVPReference Antibody 2 DRFTGSGSGADFTLTISSVQAEDLAVYYCQQHYSTPWTFGGGTKLDIKV_(L) Chain (aa) 328DIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIHWYQQKPGQPPTLLIQLASNVQReference 1 VL-VHTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPRTFGGGTKLEIKGGGGSGG scFv (aa)GGSGGGGSQIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLKWMGWINTETREPAYAYDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDYSYAMDYWGQG TSVTVSS 329QIQLVQSGPDLKKPGETVKLSCKASGYTFTNFGMNWVKQAPGKGFKWMAWINTYTGESYReference 2 VH-VLFADDFKGRFAFSVETSATTAYLQINNLKTEDTATYFCARGEIYYGYDGGFAYWGQGTLV scFv (aa)TVSAGGGGSGGGGSGGGGSDVVMTQSHRFMSTSVGDRVSITCRASQDVNTAVSWYQQKPGQSPKLLIFSASYRYTGVPDRFTGSGSGADFTLTISSVQAEDLAVYYCQQHYSTPWTFG GGTKLDIK 330CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTACAGCCAGGGCGGTCCCTGAGACTBCMA-1 scFv (nt)CTCCTGTACAGCTTCTGGATTCACCTTTGGTGATTATGCTATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTAGGTTTCATTAGAAGCAAAGCTTATGGTGGGACAACAGAATACGCCGCGTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGCATCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTGCGGCCTGGAGTGCCCCGACTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGGATATTGTGATGACCCAGTCTCCAGACTCCCTGTCTGTGTCTCCGGGCGAGAGGGCCACCATCAGCTGCAAGTCCAGCCAGAGTGTTTTATCCACCTCCAACAATAAGAACTATTTAGCTTGGTATCAGCAGAAACCAGGACAGCCCCCTAGGCTGCTCCTTTACTGGGCATCTACCCGGGAGGCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCGGTTTATTACTGTCAACAATATTTCAGTTCTCCGTACACTTTTGGCCACGGGACCAAGCTGGAAATCAAA 331GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTBCMA-2 scFv (nt)CTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTAGTGGTAGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAAAGTGGATGGCCCTCCTTCTTCTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGGAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAACAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTATTAAGACCAACTTGGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGCTGCATCCACCAGGGCCACTGGCATCCCAGACAGATTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCACCAGACTGGAGCCTGAAGATTTTGCAGTGTATTACTGTCAGCAATATGGTAGCTCACCCACTTTTGGCCGGGGGACCAAGCTG GAAATCAAA332 CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTACAGCCAGGGCGGTCCCTGAGACTBCMA-3 scFv (nt)CTCCTGTACAGCTTCTGGATTCACCTTTGGTGATTATGCTATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTAGGTTTCATTAGAAGCAAAGCTTATGGTGGGACAACAGAATACGCCGCGTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGCATCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTGCGGCCTGGAGTGCCCCGACTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGGATATTGTGATGACCCAGTCTCCAGACTCCCTGGTTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTACACAGCTCCAACAATAAGAATTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGGTTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAGTATTATACTACTCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAAATCAAA 333CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTACAGCCAGGGCGGTCCCTGAGACTBCMA-4 scFv (nt)CTCCTGTACAGCTTCTGGATTCACCTTTGGTGATTATGCTATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTAGGTTTCATTAGAAGCAAAGCTTATGGTGGGACAACAGAATACGCCGCGTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGCATCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTGCGGCCTGGAGTGCCCCGACTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGGCCATCCGGATGACCCAGTCTCCATCCTCCCTGTCCGCGTCTCTGGGGGACAGAGTCACCATCACTTGCCGGGCGAGTCAGGACATTAGGAATTCTTTGGCCTGGTATCAGCAGAGGCCAGGGAAAGCCCCTAAACTCCTGCTTTCTGCTGCATCCAGATTGGAAAGTGGGGTCCCTTCTAGGTTCAGTGGCACTACTTCTGGGGCGGAGTATGCTCTCAGCATCAGCAGCCTGCAGCCTGAAGATGTCGCATCTTATTTCTGTCAGCAGTATTATAGTCTCCCTCTCTCCTTCGGCGGAGGGACCAAG GTGGAAATCAAA334 CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTACAGCCAGGGCGGTCCCTGAGACTBCMA-5 scFv (nt)CTCCTGTACAGCTTCTGGATTCACCTTTGGTGATTATGCTATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTAGGTTTCATTAGAAGCAAAGCTTATGGTGGGACAACAGAATACGCCGCGTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGCATCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTGCGGCCTGGAGTGCCCCGACTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGGACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTACTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGATATCAAA 335CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTACAGCCAGGGCGGTCCCTGAGACTBCMA-6 scFv (nt)CTCCTGTACAGCTTCTGGATTCACCTTTGGTGATTATGCTATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTAGGTTTCATTAGAAGCAAAGCTTATGGTGGGACAACAGAATACGCCGCGTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGCATCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTGCGGCCTGGAGTGCCCCGACTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGGATATTGTGATGACCCAGTCTCCATCGTCCCTGTCTGTGTCTGTAGGAGAGAGAGTCACCATCACTTGTCGGGCGAGTCAGTCTATAAGTAATTCCTTAGCCTGGTATAAACAGAGACCGGGAGAAGCCCCTAAACTCCTGATACATGCTGCATCCAATGTGGAAGATGGGGTCCCTTCGAGGTTCAGCGGCAGGGGATCTGGGACAGTTTTCACTCTCGCCATCAGCAATGTACAGCCTGAAGATTTCGCAACTTACTACTGTCAGCAGAGTCACATGTACCCTCCGACTTTCGGCGGGGGGACCAAG GTGGAAATCAAA336 CAGGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTACAGCCAGGGCGGTCCCTGAGACTBCMA-7 scFv (nt)CTCCTGTACAGCTTCTGGATTCACCTTTGGTGATTATGCTATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTAGGTTTCATTAGAAGCAAAGCTTATGGTGGGACAACAGAATACGCCGCGTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGCATCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTGCGGCCTGGAGTGCCCCGACTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGGTCATCCAGTTGACCCAGTCTCCCTCCTCACTGTCTGCATCTGTAGGGGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGACATTGGCGATTATTTAGCCTGGTTTCAGCAGAGACCAGGGAAAGCCCCTAAGTCCCTGATCTATGTTGCGTCCACTTTGCAGAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACACACTTCACTCTCACCATCAACAGCCTGCAGCCTGAAGATTTTGCAACTTATTACTGCCAACAGTATCATAGTCACCCGTGGACGTTCGGCCCAGGGACCAAG GTGGATATCAAA337 CAGGTCCAGCTGGTGCAGTCTGGGGGAGGCTTGGTACAGCCAGGGCGGTCCCTGAGACTBCMA-8 scFv (nt)CTCCTGTACAGCTTCTGGATTCACCTTTGGTGATTATGCTATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTAGGTTTCATTAGAAGCAAAGCTTATGGTGGGACAACAGAATACGCCGCGTCTGTGAAAGGCAGATTCACCATCTCAAGAGATGATTCCAAAAGCATCGCCTATCTGCAAATGAACAGCCTGAAAACCGAGGACACAGCCGTGTATTACTGTGCGGCCTGGAGTGCCCCGACTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGGATATTGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTACTCCGTACACTTTTGGCCAGGGGACCAAGCTGGAAATCAAA 338GAAGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTBCMA-9 scFv (nt)CTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTAGTGGTAGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGAGTGGACGGTGACTACGTCGATGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGTCCTATGAGCTGACTCAGCCGCCCTCGGTGTCTGTGGCCCCAGGACAGACGGCCAGGGTTACCTGTGGGGCAAATAATATTGGAAGCAAAAGTGTCCACTGGTACCAGCAGAAGCCAGGCCAGGCCCCCATGCTGGTCGTCTATGATGATGACGACCGGCCCTCCGGGATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACCATCAGCGGGGTCGAGGCCGGGGATGAGGCCGACTACTTCTGTCACGTGTGGGATAGAAGTCGTGATCATTATGTCTTCGGAACTGGGACCAAGCTGACCGTCCTA 339GAAGTGCAGCTGGTGCAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTBCMA-10 scFv (nt)CTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTAGTGGTAGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGAGTGGACGGTGACTACGTCGATGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGTCCTATGAGCTGACTCAGCCGCCCTCGGTGTCTGTGGCCCCAGGACAGACGGCCAGGGTTACCTGTGGGGCAAATAATATTGGAAGCAAAAGTGTCCACTGGTACCAGCAGAAGCCAGGCCAGGCCCCCATGCTGGTCGTCTATGATGATGACGACCGGCCCTCCGGGATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACCATCAGCGGGGTCGAGGCCGGGGATGAGGCCGACTACTTCTGTCACGTGTGGGATAGAAGTCGTGATCATTATGTCTTCGGAACTGGGACCAAGCTGACCGTCCTA 340CAGGTGCAGCTGGTACAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTBCMA-11 scFv (nt)CTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCGAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTAGCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCGTGTATTACTGTGCGAGAGATCTGGGGCCCGACTACGATCCCGATGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTTTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGCTTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACATCGGAAGTAATGCTGTAAACTGGTACCAGCAGCTCCCAGGAACGGCCCCCGAAGTCCTCATCTATAATAGTCATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAATGGGCTCCAGTCTGAGGACGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAGAGGTTACGTCTTCGGAACTGGGACCAAGCTCACCGTCCTA 341GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTBCMA-12 scFv (nt)CTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTAGTGGTAGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAAAGTGGATGGCCCTCCTTCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGTCTGCCCTGACGCAGCCGCCCTCAGTGTCTGCGGCCCCAGGACAGAAGGTCACCATCTCCTGCTCTGGAAGCCGCTCCAACATTGGGAATAATTATGTATCCTGGTACCAACAGCTCCCAGGAACAGCCCCCAAACTCCTCATTTATGACAATGCTAAGCGACCCTCAGGAATTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACGTCAGCCACCCTGGACATCGCCGGACTCCAGACTGGGGATGAGGCCGACTATTACTGTCAGGTGTGGGATAGTAGTAGTGATCATTGGGTATTCGGCGGAGGGACCAAGCTCACCGTCCTA 342CAGATGCAGCTGGTGCAGTATGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTBCMA-13 scFv (nt)CTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATGCTATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAGTAATAAATACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAAAGCTGAGGACACGGCTGTGTATTACTGTGCTACCCTACCCGGTAGAGATGGCTACCCCGGAGCCTTTGACTACAGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGGCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGAAGCGGCTCCAACATCGGAAGTAATGATGTCTCCTGGTATCAGCAGATCCCAGGAACGGCCCCCAAACTCCTCATCTACTGGAATGATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGCCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGGGTGGTTCTTGGGTGTTCGGCGGAGGGACCAAGGTCACCGTCCTA 343GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTBCMA-14 scFv (nt)CTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAGTAATAAATACTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCTACCCTACCCGGTAGAGATGGCTACCCCGGAGCCTTTGACTACAGGGGCCCGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGGCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGAAGCGGCTCCAACATCGGAAGTAATGATGTCTCCTGGTATCAGCAGATCCCAGGAACGGCCCCCAAACTCCTCATCTACTGGAATGATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCGCCTCAGCCTCTCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTATTGTGCAGCATGGGATGACAGGTTGAACGGTTTTTGGGTGTTCGGCGGAGGGACCAAGCTCACCGTCCTA 344CAGGTGCAGCTGTTGGAGTCTGGGGGAGGCCTGGTCAAGCCTGGGGGGTCCCTGAGACTBCMA-15 scFv (nt)CTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCTGTGTATTACTGTGCGAAAGATCAGTATAGCAGTAGCGCACAAAGGGCCGACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGTTCTGGCGGTGGCGGATCGCAGTCTGTGCTGACGCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGAAGCGGCTCCAACATCGGAAGTAATGATGTCTCCTGGTATCAGCAGATCCCAGGAACGGCCCCCAAACTCCTCATCTACTGGAATGATCAGCGGCCCTCAGGGGTCCCTGACCGGTTCTCAGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGTCATCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAGTGGTTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA 345GAGGTCCAGCTGGTACAGTCTGGGCCTGAGGTGAAGAAGCCTGGGACCTCAGTGAAGGTBCMA-16 scFv (nt)CTCCTGCAAGGCTTCTGGATTCACCTTTACTAGCTCTGCTATGCAGTGGGTGCGACAGGCTCGTGGACAACGCCTTGAGTGGATAGGATGGATCGTCGTTGGCAGTGGTAACACAAACTACGCACAGAAGTTCCAGGAAAGAGTCACCATTACCAGGGACATGTCCACAAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCCGAGGACACGGCCGTGTATTACTGTGCGGCAGCTCCGTATTACGATATTTTGACTGGTTATTATTTATGGGGCCAGGGAACGCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCTGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGTCTGCCCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGAAGCGGCTCCAACATCGGAAGTAATGATGTCTCCTGGTATCAGCAGATCCCAGGAACGGCCCCCAAACTCCTCATCTACTGGAATGATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTACTGTGCATCATGGGATGACAGCCTGAGTGGTTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA 346CAGGTTCAGCTGGTGCAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTBCMA-17 scFv (nt)CTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCTGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTAGTGGTAGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGAGAGGCCGATAGTAGCGCTGACTACTGGGGCCAGGGAACCCTGGTCAACGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGCCTGTGCTGACTCAGCCACCCTCGGTGTCAGTGGCCCCAGGAAAGACGGCCATGATTACCTGTGGGGGAAACAACATTGGATTTAAAGGTGTGCAGTGGTACCAGCAGAAGACAGGCCAGGCCCCTGTGCTGGTCGTCTATGATGATAGCGACCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTCTGGGAACACGGCCACCCTGACCATCAGCAGGGTCGAAGCCGGGGATGAGGCCGATTATTACTGTCAGGTGTGGGATAGTGCTAGTGATCATTGGGTGTTCGGCGGAGGGACCAAG CTGACCGTCCTA347 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTBCMA-18 scFv (nt)CTCCTGTGCAGCCTCTGGATTCACGTTTAGTAGCTATTGGATGAGCTGGCACCGCCAGGCTCCAGGGAAGGGGCCGGAGTGGGTGGCCCACATAAACCAAGACGGAAGTGAGAAGTACTATGTGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCGAGAGTTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGGTGGCTGGCGGTTACTAACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGTCTGTGTTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGAAGCGGCTCCAACATCGGAAGTAATGATGTCTCCTGGTATCAGCAGATCCCAGGGACGGCCCCCAAACTCCTCATCTACTGGAATGATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAATGGTTGGGTGTTCGGCGGAGGGACCAAG CTGACCGTCCTA348 CAGGTCCAGCTGGTACAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTBCMA-19 scFv (nt)CTCCTGCAAGGCTTCTGGATACACCTTCACCAGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGATGGATCAACCCTAACAGTGGTGGCACAAACTATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACACGTCCATCAGCACAGCCTACATGGAGCTGAGCAGGCTGAGATCTGACGACACGGCCGTGTATTACTGTGCGAGAGATGGTGGGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGGCTGTGCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACCATCTCCTGCACTGGAACCAGCAGTGACGTTGGTGATTATAACTATGTCGCCTGGTATCAACAACACCCAGGCAAAGACCCCAAACTCATGATTTTTGAGGTCATTAATCGGCCCTCAGGGGTTTCTGATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCTCCCTGGACATCTCTGGGCTCCAGCCTGAGGACGAGGCTGATTATTACTGCATCTCATATTCACGAGGCAGCACTCCTTATGTCATCGGAACTGGGACCAAG GTGACCGTCCTA349 GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGCAGGTCCCTGAGACTBCMA-20 scFv (nt)CTCCTGTGCAGCCTCTGGATTCACCTTTGATGATTATGCCATGCACTGGGTCCGGCAAGCTCCAGGGAAGGGCCTGGAGTGGGTCTCAGGTATTAGTTGGAATAGTGGTAGCATAGGCTATGCGGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAACGCCAAGAACTCCCTGTATCTGCAAATGAACAGTCTGAGAGCTGAGGACACGGCCTTGTATTACTGTGCAAAGGGGGGCCTAGGAATAACCCCATACTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGCCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCGGGAGGCAAGACTGTAAACTGGTTCCGGCAGGTCCCAGGAACGGCCCCCCAACTCCTCATCTATAGTAATGATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCTCCTCAGCCTCCCTGGACATCAGTGGGCTCCAGTCTGAGGATGAGGCTTATTATTACTGTGGATCATGGGATGACAGCCTCAATGCTTGGGTGTTCGGCGGAGAGACCAAG CTGACCGTCCTA350 GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAAACTBCMA-21 scFv (nt)CTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTAGTGGTAGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAAAGTAGACGGAGGCTACACAGAGGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGTCTGTGCTGACTCAGCCACCCTCAGCGTCTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGTTCTGGAAGCGGCTCCAACATCGGAAGTAATGATGTCTCCTGGTATCAGCAGATCCCAGGAACGGCCCCCAAACTCCTCATCTACTGGAATGATCAGCGGCCCTCAGGGGTCCCTGACCGGTTCTCAGGCTCCAAGTCTGGCATCTCAGCCTCCCTGGCCATCAGCGGGCTCCGGTCCGAGGATGAGGCTGATTATTACTGTGCAGCATGGGATGACAGCCTGAATGGTTATGTCTTCGGAACTGGGACCAAGGTCACCGTCCTA 351GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTBCMA-22 scFv (nt)CTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTAGTGGTAGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAAAGTAGACGGAGACTACACAGAGGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACTATCTCCTGCACTGGAAGCAGCAGTGATGTTGGCAAATATAATCTTGTCTCCTGGTACCAACAGCCCCCAGGCAAAGCCCCCAAGCTCATAATTTATGACGTCAATAAGCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCACCCTGACAATCTCTGGGCTCCAGGGTGACGACGAGGCTGATTATTATTGTTGCTCATATGGAGGTAGTAGGTCTTATGTCTTCGGAACTGGGACCAAGGTGACCGTCCTA 352GAAGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTBCMA-23 scFv (nt)CTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTAGTGGTAGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAAAGTAGACGGAGACTACACAGAGGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGTCTGCCCTGACTCAGCCTGCCTCCGTGTCTGGGTCTCCTGGACAGTCGATCACTATCTCCTGCACTGGAAGCAGCAGTGATGTTGGCAAATATAATCTTGTCTCCTGGTACCAACAGCCCCCAGGCAAAGCCCCCAAGCTCATAATTTATGACGTCAATAAGCGGCCCTCAGGGGTTTCTAATCGCTTCTCTGGCTCCAAGTCTGGCAACACGGCCACCCTGACAATCTCTGGGCTCCAGGGTGACGACGAGGCTGATTATTATTGTAGCTCATATGGAGGTAGTAGGTCTTATGTCTTCGGAACTGGGACCAAGGTGACCGTCCTA 353 X₁X₂X₃MX₄ Consensus CDR-H1 X₁ = D or S;X₂ = Y or S; X₃ = A, G, W, or Y; X₄ = H, Q, or S 354X₁IX₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁YX₁₂ X₁₃ X₁₄ X₁₅ X₁₆ X₁₇ Consensus CDR-H2X₁ = F, G, H, V, W or Y; X₂ = N, R, S or V; X₃ = P, Q, S, V, W or Y;X₄ = K or null; X₅ = A or null; X₆ = D, G, N, S, or Y; X₇ = G or S;X₈ = G or S; X₉ = E, G, N, T or S; X₁₀ = I, K, or T; X₁₁ = E, G, N or Y;X₁₂ = A or V; X₁₃ = A, D or Q; X₁₄ = K or S; X₁₅ = F or V; X₁₆ = K or Q;X₁₇ = E or G 355 X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃X₁₄ Consensus CDR-H3X₁ = A, D, E, G, L, V or W; X₂ = A, D, G, L, P, Q or S;X₃ = A, D, G, L or Y; X₄ = D, G, P, R, S, V, Y or null;X₅ = D, I, P, S, T, Y or null; X₆ = A, G, I, S, T, V, Y or null;X₇ = A, D, E, F, L, P, S, Y or null; X₈ = P, Q, T, Y or null;X₉ = D, G, R, Y or null; X₁₀ = A, F, Y or null; X₁₁ = D, F or null;X₁₂ = F or null; X₁₃ = D, T or Y; X₁₄ = I, L, N, V or Y 356X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂X₁₃X₁₄ X₁₅ X₁₆ X₁₇ Consensus CDR-L1X₁ = G, K, R, S or T; X₂ = A, G or S; X₃ = G, N, S or T;X₄ = G, K, N, Q, R or S; X₅ = S or null; X₆ = D, N, V or null;X₇ = L, V or null; X₈ = H, S, Y or null; X₉ = S, T or null;X₁₀ = S or null; X₁₁ = D, G, I, N, S or null;X₁₂ = D, E, G, K, I, N or null; X₁₃ = F, G, K, N, R, S, Y or null;X₁₄ = D, K, N, T or null; X₁₅ = A, D, G, L, N, S, T or Y; X₁₆ = L or V;X₁₇ = A, H, N, Q or S 357 X₁X₂X₃X₄X₅X₆X₇ Consensus CDR-L2X₁ = A, D, E, N, S, V or W; X₂ = A, D, N, S or V;X₃ = A, D, H, I, N or S; X₄ = D, K, N, Q, R or T; X₅ = L, R or V;X₆ = A, E, P or Q; X₇ = A, D, S or T 358 X₁X₂X₃X₄X₅X₆X₇X₈X₉X₁₀X₁₁X₁₂Consensus CDR-L3 X₁ = A, C, G, H, I, Q or S; X₂ = A, Q, S or V;X₃ = S, W or Y; X₄ = D, F, G, H or Y; X₅ = D, G, M, R, S or T;X₆ = A, G, H, L, R, S, T or Y; X₇ = L, P, R, S or null;X₈ = D, G, N, R, S, T or null; X₉ = A, G, H, L, P or null;X₁₀ = F, S or null; X₁₁ = L, P, W or Y; X₁₂ = S, T or V 359 GGGGS4GS linker (aa) 360 GGGS 3GS linker (aa) 361 GGGGSGGGGSGGGGS(4GS)₃ linker (aa) 362 GSTSGSGKPGSGEGSTKG Linker (aa) 363 ESKYGPPCPPCPSpacer (IgG4hinge) (aa) 364 gaatctaagtacggaccgccctgccccccttgccctSpacer (IgG4hinge) (nt) 365ESKYGPPCPPCPGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPHinge-CH3 spacer (aa)ENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG K 366ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWHinge-CH2-CH3 spacerYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTI (aa)SKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 367MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTC Human BCMA;LGLSLIISLAVFVLMFLLRKISSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRG GenBank No.LEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEI BAB60895.1EKSISAR 368 MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTCHuman BCMA; NCBILGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGNo. NP_001183.2LEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEI EKSISAR 369MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNARSGLLGMANIDLEKSRHuman BCMA Variant;TGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKS GenBank No.LPAALSATEIEKSISAR ABN42510.1 370MAQQCFHSEYFDSLLHACKPCHLRCSNPPATCQPYCDPSVTSSVKGTYTVLWIFLGLTLMouse BCMA; NCBIVLSLALFTISFLLRKMNPEALKDEPQSPGQLDGSAQLDKADTELTRIRAGDDRIFPRSLNo. NP_035738.1EYTVEECTCEDCVKSKPKGDSDHFFPLPAMEEGATILVTTKTGDYGKSSVPTALQSVMG MEKPTHTR 371MLQMARQCSQNEYFDSLLHDCKPCQLRCSSTPPLTCQRYCNASMTNSVKGMNAILWTCLCynomolgus BCMA;GLSLIISLAVFVLTFLLRKMSSEPLKDEFKNTGSGLLGMANIDLEKGRTGDEIVLPRGL GenBank No.EYTVEECTCEDCIKNKPKVDSDHCFPLPAMEEGATILVTTKTNDYCNSLSAALSVTEIE EHH60172.1KSISAR 372 GISWNSGSIXYADSVKG BCMA-28 CDR-H2 (aa) Kabat numbering 373YISGSGSTIYYADSVKG BCMA-33 CDR-H2 (aa) Kabat numbering 374YISSSGNTIYYADSVKG BCMA-41 CDR-H2 Kabat numbering 375 CIPCQLRhuman BCMA epitope (residues 21-27) 376 DLGPPYGDDAFDIBCMA-24, -28, -29,  -39 CDR-H3 (aa) 377 DLDPDDAFDI BCMA-30 CDR-H3 (aa)378 VDGDYDDY BCMA-35 CDR-H3 (aa) 379 SNTPPLTCQR human BCMA epitope(residues 30-39) 380 RASQGISNYLA BCMA-25 CDR-L1 (aa) 381RSSQSLLHSNGYNYLD BCMA-28 CDR-L1 (aa) 382 TGTSSDVGSYNLVS BCMA-29 CDR-L1(aa) 383 RASQPIRSNLA BCMA-30 CDR-L1 (aa) 384 KSSQSVLNSSNNKNYVABCMA-31 CDR-L1 (aa) 385 GGNNIGSKGVH BCMA-32 CDR-L1 (aa) 386 RASQSISNYLABCMA-34 CDR-L1 (aa) 387 GSSTGPVTSAHSPS BCMA-36 CDR-L1 (aa) 388GSSTGAVTNGHSPY BCMA-37, -38  CDR-L1 (aa) 389 RASQGIRYELX BCMA-39 CDR-L1(aa) 390 TGSSSDVSKYNLVS BCMA-40 CDR-L1 (aa) 391 SGSSSNIGGNSVDBCMA-41 CDR-L1 (aa) 392 RASQGIGNGLA BCMA-42 CDR-L1 (aa) 393 SVTNSVKhuman BCMA epitope (residues 44-50) 394 KSSQNLLYSSNNKNYLA BCMA-44 CDR-L1(aa) 395 RASQGIGRSLA BCMA-45 CDR-L1 (aa) 396 GGNNIGSKSVH BCMA-47, -48 CDR-L1 (aa) 397 GGDQIGRKSVH BCMA-49 CDR-L1 (aa) 398 RASQNIGDWLABCMA-51 CDR-L1 (aa) 399 WGSTRES BCMA-24 CDR-L2 (aa) 400 SASTLQSBCMA-25 CDR-L2 (aa) 401 LGSNRAS BCMA-28 CDR-L2 (aa) 402 EVSKRPSBCMA-29 CDR-L2 (aa) 403 SASTRAT BCMA-30 CDR-L2 (aa) 404 DASNRATBCMA-34 CDR-L2 (aa) 405 ETTNRHS BCMA-36 CDR-L2 (aa) 406 DTTNRHSBCMA-37 CDR-L2 (aa) 407 DTNNRHS BCMA-38 CDR-L2 (aa) 408 AASTLQSBCMA-39 CDR-L2 (aa) 409 ANDRRPS BCMA-41 CDR-L2 (aa) 410 CSQNEYFhuman BCMA epitope (residues 8-14) 411 DASSLRS BCMA-45 CDR-L2 (aa) 412YDTDRPS BCMA-47, -48  CDR-L2 (aa) 413 YDSDRPS BCMA-49 CDR-L2 (aa) 414GASILES BCMA-51 CDR-L2 (aa) 415 QQYISLPWT BCMA-24 CDR-L3 (aa) 416QQSYTSRQT BCMA-25 CDR-L3 (aa) 417 MQALQTPPWT BCMA-28 CDR-L3 (aa) 418CSYAGSSTSRDV BCMA-29 CDR-L3 (aa) 419 RHYAPLT BCMA-30 CDR-L3 (aa) 420QQRSNWPPYT BCMA-34 CDR-L3 (aa) 421 HLWDRSRDHYV BCMA-26, -35  CDR-L3 (aa)422 LLSSGDARMV BCMA-36 CDR-L3 (aa) 423 SLSHAGDRVF BCMA-37 CDR-L3 (aa)424 LLSYSDARLA BCMA-38 CDR-L3 (aa) 425 LQHNSYPLT BCMA-39 CDR-L3 (aa) 426ESWDDALNGHV BCMA-41 CDR-L3 (aa) 427 QQYVEDALT BCMA-42 CDR-L3 (aa) 428LLHACIPCQLR human BCMA epitope (residues 17-27) 429 QQYYSSPYTBCMA-44 CDR-L3 (aa) 430 QQLNGYPWT BCMA-45 CDR-L3 (aa) 431 QLWDSDSDDFABCMA-47 CDR-L3 (aa) 432 QVWDSSTGQYVV BCMA-49 CDR-L3 (aa) 433 QKYDGAPPWTBCMA-51 CDR-L3 (aa) 434 EVQLLESGGGLVQPGRSLRLSCVASGFTFD BCMA-27 VH FR1(aa) 435 QVQLVQSGGGLVQPGRSLRLSCAASGFTFG BCMA-30 VH FR1 (aa) 436EVQLVQSGGGLVQPGRSLRLSCTASGFTFG BCMA-25, -31, -44,  -51 VH FR1 (aa) 437QVQLVESGGGLVKPGGSLRLSCAASGFTFS BCMA-32, -49 VH FR1 (aa) 438TGQLVQSGGGLVQPGRSLRLSCAASGFTFD BCMA-34 VH FR1 (aa) 439EVQLLESGGGLVQPGRSLRLSCTASGFTFG BCMA-42 VH FR1 (aa) 440tcctatgagctgactcagccaccctcagcgtctgggacccccgggcagagggtcaccatBCMA-52 scFv (nt)gtcttgttctggaaccagctccaacatcggaagtcactctgtaaactggtaccagcagctcccaggaacggcccccaaactcctcatctatactaataatcagcggccctcaggggtccctgaccgattctctggctccaagtctggcacctcagcctccctggccatcagtggcctccagtctgaggatgaggctgattattactgtgcagcatgggatggcagcctgaatggtctggtattcggcggagggaccaagctgaccgtcctaggttctagaggtggtggtggtagcggcggcggcggctctggtggtggtggatccctcgagatggccgaggtgcagctggtgcagtctggagcagaggtgaaaaagcccggggagtctctgaagatctcctgtaagggttctggatacagctttaccagctactggatcggctgggtgcgccagatgcccgggaaaggcctggagtggatggggatcatctatcctggtgactctgataccagatacagcccgtccttccaaggccacgtcaccatctcagctgacaagtccatcagcactgcctacctgcagtggagcagcctgaaggcctcggacaccgccatgtattactgtgcgcgctactctggttctttcgataactggggtcaaggtactctggtgaccgtctcctcagc 441RFTISRDNAKSSLYLQMNSLRAEDTAVYYCAR BCMA-37 VH FR3 (aa) 442SYELTOPPSASGTPGQRVTMSCSGTSSNIGSHSVNWYQQLPGTAPKLLIYTNNQRPSGVBCMA-52 scFv (aa)PDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDGSLNGLVFGGGTKLTVLGSRGGGGSGGGGSGGGGSLEMAEVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGHVTISADKSISTAYLQWSSLKASDTAMYYCARYSGSFD NWGQGTLVTVSS443 DSPSPGTTPKNSLYLQMNSLRAEDTAVYYCAK BCMA-47 VH FR3 (aa) 444 GGQGTMVTVSSBCMA-28 VH FR4 (aa) 445 WRQGTMVTVSS BCMA-47 VH FR4 (aa) 446DIQMTQSPAFLSASVGDRVTVTC BCMA-25 VL FR1 (aa) 447 DIVMTQSPLSLSVTPGEPASISCBCMA-28 VL FR1 (aa) 448 QPVLTQPASVSGSPGQSITISC BCMA-29 VL FR1 (aa) 449EIVLTQSPATLSVSPGERATLSC BCMA-30 VL FR1 (aa) 450 DVVMTQSPDSLAVSLGERATISCBCMA-31 VL FR1 (aa) 451 QTVVTQPPSVSVAPGQTARITC BCMA-32 VL FR1 (aa) 452EIVMTQSPATLSLSPGDRATLSC BCMA-34 VL FR1 (aa) 453 NFMLTQPPSVSVAPGQTARITCBCMA-35 VL FR1 (aa) 454 QSVLTQEPSLTVSPGETVTLTC BCMA-36 VL FR1 (aa) 455QLVLTQEPSLTVSPGGTVTLTC BCMA-37 VL FR1 (aa) 456 QAVLTQEPSLTVSPGGTVTLTCBCMA-38 VL FR1 (aa) 457 DIQXTQSPSSLSASVGDRVTITC BCMA-39 VL FR1 (aa) 458QPVLTQPPSVSGTPGQRVTIPC BCMA-41 VL FR1 (aa) 459 DIQMTQSPSLVSASVGDRVTITCBCMA-42 VL FR1 (aa) 460cagtctgccctgacacagcctgccagcgttagtgctagtcccggacagtctatcgccatBCMA-55 scFv (nt)cagctgtaccggcaccagctctgacgttggctggtatcagcagcaccctggcaaggcccctaagctgatgatctacgaggacagcaagaggcccagcggcgtgtccaatagattcagcggcagcaagagcggcaacaccgccagcctgacaattagcggactgcaggccgaggacgaggccgattactactgcagcagcaacacccggtccagcacactggtttttggcggaggcaccaagctgacagtgctgggatctagaggtggcggaggatctggcggcggaggaagcggaggcggcggatctcttgaaatggctgaagtgcagctggtgcagtctggcgccgagatgaagaaacctggcgcctctctgaagctgagctgcaaggccagcggctacaccttcatcgactactacgtgtactggatgcggcaggcccctggacagggactcgaatctatgggctggatcaaccccaatagcggcggcaccaattacgcccagaaattccagggcagagtgaccatgaccagagacaccagcatcagcaccgcctacatggaactgagccggctgagatccgacgacaccgccatgtactactgcgccagatctcagcgcgacggctacatggattattggggccagggaaccctggtcaccgtgtccagc 461 DVVMTQSPDSLAVSLGERATINC BCMA-44 VL FR1 (aa)462 AIRMTQSPSSLSASVGDRVTITC BCMA-45 VL FR1 (aa) 463QAVLTQPPSVSVAPGKTATITC BCMA-47 VL FR1 (aa) 464 QPVLTQPPSVSVAPGKTATITCBCMA-48 VL FR1 (aa) 465 LPVLTQPPSVSVAPGKTARITC BCMA-49 VL FR1 (aa) 466AIQLTQSPSTLSASVGDRVAITC BCMA-51 VL FR1 (aa) 467 WYQQKPGNAPRLLIYBCMA-25 VL FR2 (aa) 468 WYLQKPGQSPQLLIY BCMA-28 VL FR2 (aa) 469WYQQHPGKAPKLMIY BCMA-29 VL FR2 (aa) 470 WYQQKPGQAPKLLIYBCMA-30 VL FR2 (aa) 471 WYKQKPGQPPKLVIS BCMA-31 VL FR2 (aa) 472WYRQRPGQAPEVVIY BCMA-32 VL FR2 (aa) 473 WFQKKPGQAPTTLIYBCMA-36 VL FR2 (aa) 474 WFQQKPGQAPRTLIY BCMA-37, -38 VL FR2 (aa) 475WYQQKPGKAPKLLIY BCMA-39 VL FR2 (aa) 476 WFQEVPGTAPKLLIYBCMA-41 VL FR2 (aa) 477 WYQQKPGKAPKLLLF BCMA-42 VL FR2 (aa) 478QSALTQPASVSASPGQSIAISCTGTSSDVGWYQQHPGKAPKLMIYEDSKRPSGVSNRFSBCMA-55 scFv (aa)GSKSGNTASLTISGLQAEDEADYYCSSNTRSSTLVFGGGTKLTVLGSRGGGGSGGGGSGGGGSLEMAEVQLVQSGAEMKKPGASLKLSCKASGYTFIDYYVYWMRQAPGQGLESMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAMYYCARSQRDGYMDYWGQ GTLVTVSS 479WYKQKPGGVPQLLIH BCMA-45 VL FR2 (aa) 480 WYQRKPGQGPVVVIQBCMA-47, -48 VL FR2 (aa) 481 WYQQKPGQAPVLVMS BCMA-49 VL FR2 (aa) 482WYQQKPGKAPKLLIF BCMA-51 VL FR2 (aa) 483 GVPDRFSGSGSGTDFTLTISSLQAEDVAIYHCBCMA-24 VL FR3 (aa) 484 GVPSRFRGTGYGTEFSLTIDSLQPEDFATYYCBCMA-25 VL FR3 (aa) 485 GVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCBCMA-28 VL FR3 (aa) 486 GVSNRFSGSKSGNTASPTISGLQAEDEADYYCBCMA-29 VL FR3 (aa) 487 GIPDRFSGSGSGTDFTLTISRLEHEDFAVYYRBCMA-30 VL FR3 (aa) 488 GVPDRFSGSNSGNTATLTVRGVEAGDEADYYCBCMA-32 VL FR3 (aa) 489 GIPARFSGSGSGTDFTLTISSLEPEDFAVYYCBCMA-34 VL FR3 (aa) 490 WTPARFSGSLLGGKAALTLSGAQPEDEADYYCBCMA-36 VL FR3 (aa) 491 WTPARFSGSLLGGKAALTLSGAQPEDEAEYYCBCMA-37 VL FR3 (aa) 492 WTPARFSGSLLGGKAALTLSGAQPEDEADYFCBCMA-38 VL FR3 (aa) 493 GVPSRFSGSGSGTDFALTIRSLQPEDFATYYCBCMA-39 VL FR3 (aa) 494 GVPDRFSGTKSGTSASLAIRGLQSDDDAHYYCBCMA-41 VL FR3 (aa) 495 GVPSRFSGSRSGTDYTLTISSLQPEDVATYYCBCMA-42 VL FR3 (aa) 496 GYSFTSYW BCMA-52 CDR-H1 (aa) 497GVPSRFSGSGSGTEFTLTISGVQSEDSATYHC BCMA-45 VL FR3 (aa) 498GIPERFSGSKSGDTASLTISGVEAGDEADYYC BCMA-47 VL FR3 (aa) 499GIPERFSGSNSGNTATLTISRVEAGDEGDYYC BCMA-48 VL FR3 (aa) 500GIPERFSGSNSGNTATLTISRVEAGDEAAYYC BCMA-49 VL FR3 (aa) 501GVPSRFSGSGSGTDFTLTISSLOPEDVAVYYC BCMA-51 VL FR3 (aa) 502 FGPGTRLDIKBCMA-25 VL FR4 (aa) 503 FGXGTKLTVL BCMA-29 VL FR4 (aa) 504 FGQGTKLDIKBCMA-31, -34 VL FR4 (aa) 505 FGTGTKLDIK BCMA-35 VL FR4 (aa) 506FGGGTKVDIK BCMA-42 VL FR4 (aa) 507 IYPGDSDT BCMA-52 CDR-H2 (aa) 508FGQGTKVEIK BCMA-24, -28, -51 VL FR4 (aa) 509 GFTFGDYAMH BCMA-30 CDR-H1(aa) AbM numbering 510 GISWNSGSIX BCMA-28 CDR-H2 (aa) AbM numbering 511YISGSGSTIY BCMA-33 CDR-H2 (aa) AbM numbering 512 YISSSGNTIYBCMA-41 CDR-H2 AbM numbering 513 ARYSGSFDN BCMA-52 CDR-H3 (aa) 514 SWNSGBCMA-28 CDR-H2 (aa) Chothia numbering 515 SGSGST BCMA-33 CDR-H2(aa) Chothia numbering 516 SSSGNT BCMA-41 CDR-H2 Chothia numbering 517SSNIGSHS BCMA-52 CDR-L1 (aa) 518EVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSGISWNSGSIGBCMA-24 VH chainYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLGPPYGDDAFDIWGQGTMV (aa) TVSS519 EVQLVQSGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGTBCMA-25, -31, -44, TEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSS-51 VH chain (aa) 520EVQLLESGGGLVQPGRSLRLSCVASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIGBCMA-27 VH chainYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKGGLGITPYYFDYWGQGTLVT (aa) VSS 521QVQLVQSGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIXBCMA-28 VH chainYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLGPPYGDDAFDIGGQGTMV (aa) TVSS522 QVQLVQSGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIGBCMA-29, -39 VHYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLGPPYGDDAFDIWGQGTMV chain (aa)TVSS 523 QVQLVQSGGGLVQPGRSLRLSCAASGFTFGDYAMHWVRQAPGKGLEWVSGISWNSGSIGBCMA-30 VH chainYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLDPDDAFDIWGQGTMVTVS (aa) S 524QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-32, -49 VHYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGPPSFDIWGQGTMVTVSS chain (aa)525 QVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISGSGSTIYBCMA-33 VH chainYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREADSSADYWGQGTLVNVSS (aa) 526TGQLVQSGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIGBCMA-34 VH chainYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLGPDYDPDAFDIWGQGTMV (aa) TVSS527 EVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-35 VH chainYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARVDGDYDDYWGQGTLVTVSS (aa) 528QVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-36, 38 VHYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARVDGDYVDDYWGQGTLVTVSS chain (aa)529 EVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-37 VH chainYADSVKGRFTISRDNAKSSLYLQMNSLRAEDTAVYYCARVDGDYVDDYWGQGTLVTVSS (aa) 530QVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGNTIYBCMA-41 VH chainYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGDYVDDYWGQGTLVTVSS (aa) 531EVQLLESGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGTBCMA-42 VH chainTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSS (aa) 532 TNNBCMA-52 CDR-L2 (aa) 533QVQLLESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-47 VH chainYADSVKGDSPSPGTTPKNSLYLQMNSLRAEDTAVYYCAKVDGPPSFDIWRQGTMVTVSS (aa) 534DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWGSTBCMA-24 VL chain RESGVPDRFSGSGSGTDFTLTISSLQAEDVAIYHCQQYISLPWTFGQGTKVEIK(aa) 535 DIQMTQSPAFLSASVGDRVTVTCRASQGISNYLAWYQQKPGNAPRLLIYSASTLQSGVPBCMA-25 VL chain SRFRGTGYGTEFSLTIDSLQPEDFATYYCQQSYTSRQTFGPGTRLDIK (aa)536 SYVLTQPPSVSVAPGQTARITCGANNIGSKSVHWYQQKPGQAPMLVVYDDDDRPSGIPEBCMA-26 VL chain RFSGSNSGNTATLTISGVEAGDEADYFCHLWDRSRDHYVFGTGTKLTVL (aa)537 DIVMTQSPLSLSVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRBCMA-28 VL chain ASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPPWTFGQGTKVEIK(aa) 538 QPVLTQPASVSGSPGQSITISCTGTSSDVGSYNLVSWYQQHPGKAPKLMIYEVSKRPSGBCMA-29 VL chain VSNRFSGSKSGNTASPTISGLQAEDEADYYCCSYAGSSTSRDVFGXGTKLTVL(aa) 539 EIVLTQSPATLSVSPGERATLSCRASQPIRSNLAWYQQKPGQAPKLLIYSASTRATGIPBCMA-30 VL chain DRFSGSGSGTDFTLTISRLEHEDFAVYYRRHYAPLTFGGGTKVEIK (aa) 540DVVMTQSPDSLAVSLGERATISCKSSQSVLNSSNNKNYVAWYKQKPGQPPKLVISWASTBCMA-31 VL chain RESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPYTFGQGTKLDIK(aa) 541 QTVVTQPPSVSVAPGQTARITCGGNNIGSKGVHWYRQRPGQAPEVVIYDDSDRPSGVPDBCMA-32 VL chain RFSGSNSGNTATLTVRGVEAGDEADYYCQVWDSSSDHWVFGGGTKLTVL (aa)542 EIVMTQSPATLSLSPGDRATLSCRASQSISNYLAWYQQKPGQAPRLLIYDASNRATGIPBCMA-34 VL chain ARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPYTFGQGTKLDIK (aa)543 NFMLTQPPSVSVAPGQTARITCGANNIGSKSVHWYQQKPGQAPMLVVYDDDDRPSGIPEBCMA-35 VL chain RFSGSNSGNTATLTISGVEAGDEADYFCHLWDRSRDHYVFGTGTKLDIK (aa)544 QSVLTQEPSLTVSPGETVTLTCGSSTGPVTSAHSPSWFQKKPGQAPTTLIYETTNRHSWBCMA-36 VL chain TPARFSGSLLGGKAALTLSGAQPEDEADYYCLLSSGDARMVFGGGTKLTVL(aa) 545 QLVLTQEPSLTVSPGGTVTLTCGSSTGAVTNGHSPYWFQQKPGQAPRTLIYDTTNRHSWBCMA-37 VL chain TPARFSGSLLGGKAALTLSGAQPEDEAEYYCSLSHAGDRVFFGGGTKLTVL(aa) 546 QAVLTQEPSLTVSPGGTVTLTCGSSTGAVTNGHSPYWFQQKPGQAPRTLIYDTNNRHSWBCMA-38 VL chain TPARFSGSLLGGKAALTLSGAQPEDEADYFCLLSYSDARLAFGGGTKLTVL(aa) 547 DIQXTQSPSSLSASVGDRVTITCRASQGIRYELXWYQQKPGKAPKLLIYAASTLQSGVPBCMA-39 VL chain SRFSGSGSGTDFALTIRSLQPEDFATYYCLQHNSYPLTFGRGTKLEIK (aa)548 QSALTQPASVSGSPGQSITISCTGSSSDVSKYNLVSWYQQPPGKAPKLITYDVNKRPSGBCMA-40 VL chain VSNRFSGSKSGNTATLTISGLQGDDEADYYCCSYGGSRSYVFGTGTKLTVL(aa) 549 QPVLTQPPSVSGTPGQRVTIPCSGSSSNIGGNSVDWFQEVPGTAPKLLIYANDRRPSGVBCMA-41 VL chain PDRFSGTKSGTSASLAIRGLQSDDDAHYYCESWDDALNGHVFGGGTKLTVL(aa) 550 DIQMTQSPSLVSASVGDRVTITCRASQGIGNGLAWYQQKPGKAPKLLLFAASRLESGVPBCMA-42 VL chain SRFSGSRSGTDYTLTISSLQPEDVATYYCQQYVEDALTFGGGTKVDIK (aa)551 AAWDGSLNGLV BCMA-52 CDR-L3 (aa) 552DVVMTQSPDSLAVSLGERATINCKSSQNLLYSSNNKNYLAWYQQKPGQPPKLLIYWASTBCMA-44 VL chain RESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSSPYTFGQGTKLEIK(aa) 553 AIRMTQSPSSLSASVGDRVTITCRASQGIGRSLAWYKQKPGGVPQLLIHDASSLRSGVPBCMA-45 VL chain SRFSGSGSGTEFTLTISGVQSEDSATYHCQQLNGYPWTFGQGTKVDIK (aa)554 QAVLTQPPSVSVAPGKTATITCGGNNIGSKSVHWYQRKPGQGPVVVIQYDTDRPSGIPEBCMA-47 VL chain RFSGSKSGDTASLTISGVEAGDEADYYCQLWDSDSDDFAFGTGTKLTVL (aa)555 QPVLTQPPSVSVAPGKTATITCGGNNIGSKSVHWYQRKPGQGPVVVIQYDTDRPSGIPEBCMA-48 VL chain RFSGSNSGNTATLTISRVEAGDEGDYYCQVWDSSSDHWVFGGGTKLTVL (aa)556 LPVLTQPPSVSVAPGKTARITCGGDQIGRKSVHWYQQKPGQAPVLVMSYDSDRPSGIPEBCMA-49 VL chain RFSGSNSGNTATLTISRVEAGDEAAYYCQVWDSSTGQYVVFGGGTKLTVL (aa)557 AIQLTQSPSTLSASVGDRVAITCRASQNIGDWLAWYQQKPGKAPKLLIFGASILESGVPBCMA-51 VL chain SRFSGSGSGTDFTLTISSLQPEDVAVYYCQKYDGAPPWTFGQGTKVEIK (aa)558 EVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSGISWNSGSIGBCMA-24 scFv YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLGPPYGDDAFDIWGQGTMVsequence (aa)TVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWGSTRESGVPDXFSGSGSGTDFTLTISSLQAEDVAIYHCQQYISLPWTFGQGTKVEIK 559EVQLVQSGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGT BCMA-25 scFvTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSSsequence (aa)GGGGSGGGGSGGGGSDIQMTQSPAFLSASVGDRVTVTCRASQGISNYLAWYQQKPGNAPRLLIYSASTLQSGVPSRFRGTGYGTEFSLTIDSLQPEDFATYYCQQSYTSRQTFGPGTR LDIK 560EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIY BCMA-26 scFvYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGPPSFDIWGQGTMVTVSSsequence (aa)GGGGSGGGGSGGGGSSYVLTQPPSVSVAPGQTARITCGANNIGSKSVHWYQQKPGQAPMLVVYDDDDRPSGIPERFSGSNSGNTATLTISGVEAGDEADYFCHLWDRSRDHYVFGTGT KLTVL 561EVQLLESGGGLVQPGRSLRLSCVASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIG BCMA-27 scFvYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKGGLGITPYYFDYWGQGTLVTsequence (aa)VSSGGGGSGGGGSGGGGSQPVLTQPPSASGTPGQRVTISCSGGKTVNWFRQVPGTAPQLLIYSNDQRPSGVPDRFSGSKSGSSASLDISGLQSEDEAYYYCGSWDDSLNAWVFGGETK LTVL 562QVQLVQSGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIX BCMA-28 scFvYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLGPPYGDDAFDIGGQGTMVsequence (aa)TVSSGGGGSGGGGSGGGGSDIVMTQSPLSLSVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTPPWTFGQGTKVEIK 563QVQLVQSGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIG BCMA-29 scFvYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLGPPYGDDAFDIWGQGTMVsequence (aa)TVSSGGGGSGGGGSGGGGSQPVLTQPASVSGSPGQSITISCTGTSSDVGSYNLVSWYQQHPGKAPKLMIYEVSKRPSGVSNRFSGSKSGNTASPTISGLQAEDEADYYCCSYAGSSTSRDVFGXGTKLTVL 564QVQLVQSGGGLVQPGRSLRLSCAASGFTFGDYAMHWVRQAPGKGLEWVSGISWNSGSIG BCMA-30 scFvYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLDPDDAFDIWGQGTMVTVSsequence (aa)SGGGGSGGGGSGGGGSEIVLTQSPATLSVSPGERATLSCRASQPIRSNLAWYQQKPGQAPKLLIYSASTRATGIPDRFSGSGSGTDFTLTISRLEHEDFAVYYRRHYAPLTFGGGTKV EIK 565EVQLVQSGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGT BCMA-31 scFvTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSSsequence (aa)GGGGSGGGGSGGGGSDVVMTQSPDSLAVSLGERATISCKSSQSVLNSSNNKNYVAWYKQKPGQPPKLVISWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPYT FGQGTKLDIK566 QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-32 scFv YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGPPSFDIWGQGTMVTVSSsequence (aa)GGGGSGGGGSGGGGSQTVVTQPPSVSVAPGQTARITCGGNNIGSKGVHWYRQRPGQAPEVVIYDDSDRPSGVPDRFSGSNSGNTATLTVRGVEAGDEADYYCQVWDSSSDHWVFGGGT KLTVL 567QVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISGSGSTIY BCMA-33 scFvYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREADSSADYWGQGTLVNVSSGsequence (aa)GGGSGGGGSGGGGSQPVLTQPPSVSVAPGKTAMITCGGNNIGFKGVQWYQQKTGQAPVLVVYDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSASDHWVFGGGTK LTVL 568TGQLVQSGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIG BCMA-34 scFvYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLGPDYDPDAFDIWGQGTMVsequence (aa)TVSSGGGGSGGGGSGGGGSEIVMTQSPATLSLSPGDRATLSCRASQSISNYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPYTF GQGTKLDIK569 EVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIYBCMA-35 scFv YADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARVDGDYDDYWGQGTLVTVSSGsequence (aa)GGGSGGGGSGGGGSNFMLTQPPSVSVAPGQTARITCGANNIGSKSVHWYQQKPGQAPMLVVYDDDDRPSGIPERFSGSNSGNTATLTISGVEAGDEADYFCHLWDRSRDHYVFGTGTK LDIK 570QVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIY BCMA-36 scFvYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARVDGDYVDDYWGQGTLVTVSSsequence (aa)GGGGSGGGGSGGGGSQSVLTQEPSLTVSPGETVTLTCGSSTGPVTSAHSPSWFQKKPGQAPTTLIYETTNRHSWTPARFSGSLLGGKAALTLSGAQPEDEADYYCLLSSGDARMVFGG GTKLTVL 571EVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIY BCMA-37 scFvYADSVKGRFTISRDNAKSSLYLQMNSLRAEDTAVYYCARVDGDYVDDYWGQGTLVTVSSsequence (aa)GGGGSGGGGSGGGGSQLVLTQEPSLTVSPGGTVTLTCGSSTGAVTNGHSPYWFQQKPGQAPRTLIYDTTNRHSWTPARFSGSLLGGKAALTLSGAQPEDEAEYYCSLSHAGDRVFFGG GTKLTVL 572QVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIY BCMA-38 scFvYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARVDGDYVDDYWGQGTLVTVSSsequence (aa)GGGGSGGGGSGGGGSQAVLTQEPSLTVSPGGTVTLTCGSSTGAVTNGHSPYWFQQKPGQAPRTLIYDTNNRHSWTPARFSGSLLGGKAALTLSGAQPEDEADYFCLLSYSDARLAFGG GTKLTVL 573QVQLVQSGGGLVQPGRSLRLSCAASGFTFDDYAMHWVRQAPGKGLEWVSGISWNSGSIG BCMA-39 scFvYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLGPPYGDDAFDIWGQGTMVsequence (aa)TVSSGGGGSGGGGSGGGGSDIQXTQSPSSLSASVGDRVTITCRASQGIRYELXWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTDFALTIRSLQPEDFATYYCLQHNSYPLTFG RGTKLEIK 574EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIY BCMA-40 scFvYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGDYTEDYWGQGTLVTVSSsequence (aa)GGGGSGGGGSGGGGSQSALTQPASVSGSPGQSITISCTGSSSDVSKYNLVSWYQQPPGKAPKLIIYDVNKRPSGVSNRFSGSKSGNTATLTISGLQGDDEADYYCCSYGGSRSYVFGT GTKLTVL 575QVQLVQSGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGNTIY BCMA-41 scFvYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGDYVDDYWGQGTLVTVSSsequence (aa)GGGGSGGGGSGGGGSQPVLTQPPSVSGTPGQRVTIPCSGSSSNIGGNSVDWFQEVPGTAPKLLIYANDRRPSGVPDRFSGTKSGTSASLAIRGLQSDDDAHYYCESWDDALNGHVFGG GTKLTVL 576EVQLLESGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGT BCMA-42 scFvTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSSsequence (aa)GGGGSGGGGSGGGGSDIQMTQSPSLVSASVGDRVTITCRASQGIGNGLAWYQQKPGKAPKLLLFAASRLESGVPSRFSGSRSGTDYTLTISSLQPEDVATYYCQQYVEDALTFGGGTK VDIK 577EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQMPGKGLEWMGIIYPGDSDTRBCMA-52 VH (aa)YSPSFQGHVTISADKSISTAYLQWSSLKASDTAMYYCARYSGSFDNWGQGTLVTVSS 578EVQLVQSGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGT BCMA-44 scFvTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSSsequence (aa)GGGGSGGGGSGGGGSDVVMTQSPDSLAVSLGERATINCKSSQNLLYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSSPYT FGQGTKLEIK579 QVQLVQSGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGTBCMA-45 scFv TEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSSsequence (aa)GGGGSGGGGSGGGGSAIRMTQSPSSLSASVGDRVTITCRASQGIGRSLAWYKQKPGGVPQLLIHDASSLRSGVPSRFSGSGSGTEFTLTISGVQSEDSATYHCQQLNGYPWTFGQGTK VDIK 580QVQLLESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIY BCMA-47 scFvYADSVKGDSPSPGTTPKNSLYLQMNSLRAEDTAVYYCAKVDGPPSFDIWRQGTMVTVSSsequence (aa)GGGGSGGGGSGGGGSQAVLTQPPSVSVAPGKTATITCGGNNIGSKSVHWYQRKPGQGPVVVIQYDTDRPSGIPERFSGSKSGDTASLTISGVEAGDEADYYCQLWDSDSDDFAFGTGT KLTVL 581EVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIY BCMA-48 scFvYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGPPSFDIWGQGTMVTVSSsequence (aa)GGGGSGGGGSGGGGSQPVLTQPPSVSVAPGKTATITCGGNNIGSKSVHWYQRKPGQGPVVVIQYDTDRPSGIPERFSGSNSGNTATLTISRVEAGDEGDYYCQVWDSSSDHWVFGGGT KLTVL 582QVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVSYISSSGSTIY BCMA-49 scFvYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAKVDGPPSFDIWGQGTMVTVSSsequence (aa)GGGGSGGGGSGGGGSLPVLTQPPSVSVAPGKTARITCGGDQIGRKSVHWYQQKPGQAPVLVMSYDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEAAYYCQVWDSSTGQYVVFGGG TKLTVL 583EVQLVQSGGGLVQPGRSLRLSCTASGFTFGDYAMSWFRQAPGKGLEWVGFIRSKAYGGT BCMA-51 scFvTEYAASVKGRFTISRDDSKSIAYLQMNSLKTEDTAVYYCAAWSAPTDYWGQGTLVTVSSsequence (aa)GGGGSGGGGSGGGGSAIQLTQSPSTLSASVGDRVAITCRASQNIGDWLAWYQQKPGKAPKLLIFGASILESGVPSRFSGSGSGTDFTLTISSLQPEDVAVYYCQKYDGAPPWTFGQGT KVEIK 584CAGGTGCAGCTGGTGCAATCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACT BCMA-41 scFvCTCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCCGCCAGGsequence (nt)CTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTAGTGGTAATACCATATACTACGCAGACTCTGTAAAGGGCCGATTCACCATCTCCAGGGACAACGCCAAAAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAAAGTGGACGGTGACTACGTCGATGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGATCGCAGCCTGTGCTGACTCAGCCACCCTCAGTGTCTGGGACCCCCGGGCAGAGGGTCACCATCCCTTGTTCTGGAAGCAGCTCCAACATCGGAGGTAACTCTGTAGACTGGTTCCAGGAGGTCCCAGGGACGGCCCCCAAACTCCTCATCTACGCTAATGATCGGCGGCCCTCGGGTGTCCCTGACCGCTTCTCTGGCACCAAGTCGGGCACCTCAGCCTCCCTGGCCATCAGGGGGCTCCAGTCTGACGATGACGCTCATTATTACTGTGAATCCTGGGACGATGCCCTGAACGGTCACGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA 585QIQLVQSGPELKKPGETVKISCKASGYTFTDYSINWVKRAPGKGLKWMGWINTETREPAReference 1 VH-VLYAYDFRGRFAFSLETSASTAYLQINNLKYEDTATYFCALDYSYAMDYWGQGTSVTVSSG scFv (aa)GGGSGGGGSGGGGSDIVLTQSPPSLAMSLGKRATISCRASESVTILGSHLIHWYQQKPGQPPTLLIQLASNVQTGVPARFSGSGSRTDFTLTIDPVEEDDVAVYYCLQSRTIPRTFGG GTKLEIK 586DVVMTQSHRFMSTSVGDRVSITCRASQDVNTAVSWYQQKPGQSPKLLIFSASYRYTGVPReference 2 VL-VHDRFTGSGSGADFTLTISSVQAEDLAVYYCQQHYSTPWTFGGGTKLDIKGGGGSGGGGSG scFv (aa)GGGSQIQLVQSGPDLKKPGETVKLSCKASGYTFTNFGMNWVKQAPGKGFKWMAWINTYTGESYFADDFKGRFAFSVETSATTAYLQINNLKTEDTATYFCARGEIYYGYDGGFAYWGQ GTLVTVSA 587SYELTQPPSASGTPGQRVTMSCSGTSSNIGSHSVNWYQQLPGTAPKLLIYTNNQRPSGVBCMA-52 VL (aa) PDRFSGSKSGTSASLAISGLQSEDEADYYCAAWDGSLNGLVFGGGTKLTVLG 588GYTFIDYY BCMA-55 CDR-H1 (aa) 589 INPNSGGT BCMA-55 CDR-H2 (aa) 590ARSQRDGYMDY BCMA-55 CDR-H3 (aa) 591 ISCTGTSSD BCMA-55 CDR-L1 (aa) 592EDS BCMA-55 CDR-L2 (aa) 593 SSNTRSSTLV BCMA-55 CDR-L3 (aa) 594EVQLVQSGAEMKKPGASLKLSCKASGYTFIDYYVYWMRQAPGQGLESMGWINPNSGGTNBCMA-55 VH (aa)YAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAMYYCARSQRDGYMDYWGQGTLVTVSS 595QSALTQPASVSASPGQSIAISCTGTSSDVGWYQQHPGKAPKLMIYEDSKRPSGVSNRFSBCMA-55 VL (aa) GSKSGNTASLTISGLQAEDEADYYCSSNTRSSTLVFGGGTKLTVLG 596LEGGGEGRGSLLTCGDVEENPGPR T2A 597 EGRGSLLTCGDVEENPGP T2A 598GSGATNFSLLKQAGDVEENPGP P2A 599 ATNFSLLKQAGDVEENPGP P2A 600QCTNYALLKLAGDVESNPGP E2A 601 VKQTLNFDLLKLAGDVESNPGP F2A 602MLLLVTSLLLCELPHPAFLLIPRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLH EGFRtILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIG LFM 603RKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQEL EGFRtDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFM 604GAGGTGCAGCTGGTGCAGAGCGGAGGAGGCCTGGTGCAGCCTGGCAGGTCCCTGCGCCT BCMA-25 scFvGTCTTGCACCGCCAGCGGCTTCACATTTGGCGACTATGCCATGTCCTGGTTCAGGCAGGsequence (nt)CACCAGGCAAGGGCCTGGAGTGGGTGGGCTTTATCCGCTCTAAGGCCTACGGCGGCACCACAGAGTATGCCGCCAGCGTGAAGGGCCGGTTCACCATCAGCCGGGACGACTCTAAGAGCATCGCCTACCTGCAGATGAACTCTCTGAAGACCGAGGACACAGCCGTGTACTATTGCGCAGCATGGAGCGCCCCAACCGATTATTGGGGCCAGGGCACCCTGGTGACAGTGAGCTCCGGCGGCGGCGGCTCTGGAGGAGGAGGAAGCGGAGGAGGAGGATCCGACATCCAGATGACACAGTCCCCTGCCTTTCTGTCCGCCTCTGTGGGCGATAGGGTGACCGTGACATGTCGCGCCTCCCAGGGCATCTCTAACTACCTGGCCTGGTATCAGCAGAAGCCCGGCAATGCCCCTCGGCTGCTGATCTACAGCGCCTCCACCCTGCAGAGCGGAGTGCCCTCCCGGTTCAGAGGAACCGGCTATGGCACAGAGTTTTCTCTGACCATCGACAGCCTGCAGCCAGAGGATTTCGCCACATACTATTGTCAGCAGTCTTACACCAGCCGGCAGACATTTGGCCCCGGCACAAGA CTGGATATCAAG605 GAGGTGCAGCTGGTGGAGTCCGGAGGAGGCCTGGTGAAGCCAGGAGGCTCTCTGAGGCTBCMA-26 scFv GAGCTGCGCAGCCTCCGGCTTCACCTTTTCTGACTACTATATGAGCTGGATCAGGCAGGsequence (nt)CACCAGGCAAGGGCCTGGAGTGGGTGTCTTACATCAGCTCCTCTGGCAGCACAATCTACTATGCCGACTCCGTGAAGGGCAGGTTCACCATCTCTCGCGATAACGCCAAGAATAGCCTGTATCTGCAGATGAACTCCCTGCGGGCCGAGGATACAGCCGTGTACTATTGCGCCAAGGTGGACGGCCCCCCTTCCTTTGATATCTGGGGCCAGGGCACAATGGTGACCGTGAGCTCCGGAGGAGGAGGATCCGGCGGAGGAGGCTCTGGCGGCGGCGGCTCTAGCTATGTGCTGACCCAGCCACCATCCGTGTCTGTGGCACCTGGACAGACAGCAAGGATCACCTGTGGAGCAAACAATATCGGCAGCAAGTCCGTGCACTGGTACCAGCAGAAGCCTGGCCAGGCCCCAATGCTGGTGGTGTATGACGATGACGATCGGCCCAGCGGCATCCCTGAGAGATTTTCTGGCAGCAACTCCGGCAATACCGCCACACTGACCATCTCTGGAGTGGAGGCAGGCGACGAGGCAGATTACTTCTGTCACCTGTGGGACCGGAGCAGAGATCACTACGTGTTCGGCACAGGCACCAAGCTGACCGTGCTG 606tcctatgagctgactcagccaccctcagcgtctgggacccccgggcagagggtcaccat BCMA-52 scFvgtcttgttctggaaccagctccaacatcggaagtcactctgtaaactggtaccagcagcsequence (nt)tcccaggaacggcccccaaactcctcatctatactaataatcagcggccctcaggggtccctgaccgattctctggctccaagtctggcacctcagcctccctggccatcagtggcctccagtctgaggatgaggctgattattactgtgcagcatgggatggcagcctgaatggtctggtattcggcggagggaccaagctgaccgtcctaggttctagaggtggtggtggtagcggcggcggcggctctggtggtggtggatccctcgagatggccgaggtgcagctggtgcagtctggagcagaggtgaaaaagcccggggagtctctgaagatctcctgtaagggttctggatacagctttaccagctactggatcggctgggtgcgccagatgcccgggaaaggcctggagtggatggggatcatctatcctggtgactctgataccagatacagcccgtccttccaaggccacgtcaccatctcagctgacaagtccatcagcactgcctacctgcagtggagcagcctgaaggcctcggacaccgccatgtattactgtgcgcgctactctggttctttcgataactggggtcaaggtactctggtgaccgtctcctca 607caatctgccctgactcagcctgcctccgtgtctgcgtctcctggacagtcgat BCMA-55 scFvcgccatctcctgcactggaaccagcagtgacgttggttggtatcaacagcacc sequence (nt)caggcaaagcccccaaactcatgatttatgaggacagtaagcggccctcaggggtttctaatcgcttctctggctccaagtctggcaacacggcctccctgaccatctctgggctccaggctgaggacgaggctgattattactgcagctcaaatacaagaagcagcactttggtgttcggcggagggaccaagctgaccgtcctaggttctagaggtggtggtggtagcggcggcggcggctctggtggtggtggatccctcgagatggccgaagtgcagctggtgcagtctggggctgagatgaagaagcctggggcctcactgaagctctcctgcaaggcttctggatacaccttcatcgactactatgtatactggatgcgacaggcccctggacaagggcttgagtccatgggatggatcaaccctaacagtggtggcacaaactatgcacagaagtttcagggcagggtcaccatgaccagggacacgtccatcagcacagcctacatggagctgagcaggctgagatctgacgacaccgccatgtattactgtgcgcgctcccagcgtgacggttacatggattactggggtcaaggtactctggtgaccgtctcctca 608 SNTPPLTCQR BCMA epitope609 CIPCQLR BCMA epitope 610 SVTNSVK BCMA epitope 611 CSQNEYFBCMA epitope 612 LLHACIPCQLR BCMA epitope 613 QNEYF BCMA epitope 614CIPCQL BCMA epitope 615 CQRYC BCMA epitope 616 MLMAG BCMA epitope 617QNEYFDSLL BCMA epitope 618 YFDSL BCMA epitope 619 QLRCSSNTPPLBCMA epitope 620 YFDSLL BCMA epitope

What is claimed:
 1. A method of treatment, the method comprisingadministering to a subject having a disease or disorder associated withBCMA an engineered cell comprising a chimeric antigen receptor (CAR)comprising an extracellular domain comprising an anti-BCMA antibody orantigen-binding fragment, a transmembrane domain, and an intracellularsignaling region comprising an intracellular signaling domain, whereinthe anti-BCMA antibody or antigen-binding fragment comprises a heavychain variable (V_(H)) region and a light chain variable (V_(L)) region,wherein: the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:110,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:116; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:111, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:117; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:110, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:118; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:110,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:119; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:110, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:120; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:110, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:121; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:110,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:122; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:110, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:123; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:112, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:124; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:113,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:125; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:114, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:126; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:115, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:127; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:247,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:257; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:248, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:258; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:249, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:259; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:250,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:260; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:251, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:261; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:252, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:262; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:253,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:263; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:254, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:264; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:255, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:265; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:256,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:266; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:256, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:267; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:518, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:534; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:519,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:535; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:115, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:536; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:520, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:264; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:521,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:537; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:522, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:538; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:523, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:539; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:519,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:540; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:524, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:541; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:525, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:261; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:526,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:542; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:527, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:543; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:528, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:544; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:529,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:545; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:528, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:546; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:522, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:547; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:256,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:548; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:530, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:549; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:531, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:550; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:519,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:552; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:110, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:553; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:110, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:118; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:533,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:554; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:115, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:555; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:524, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:556; or the V_(H) region comprises a CDR-H1, CDR-H2 andCDR-H3 contained within the V_(H) region amino acid sequence of SEQ IDNO:519, and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3contained within the V_(L) region amino acid sequence of SEQ ID NO:557,respectively.
 2. The method of claim 1, wherein: the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:26, 37, and 47, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 8, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:27, 38, and 48, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:28, 39, and 49, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:29, 40, and 50, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:30, 39, and 51, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:31, 41, and 52, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:32, 42, and 53, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:30, 39, and 54, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 9, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:33, 43, and 55, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 10, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:34, 44, and 56, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 6, and 11, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:35, 45, and 57, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 10, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:36, 46, and 58, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:140, 145, and 149, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:174, 179, and 184, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:141, 145, and 149, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:174, 179, and 185, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:141, 145, and 150, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:174, 179, and 186, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:142, 146, and 151, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:174, 179, and 187, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 152, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:175, 180, and 188, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:143, 147, and 153, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:174, 179, and 189, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:144, 148, and 154, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:176, 181, and 190, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 6, and 155, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:177, 182, and 191, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 156, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:174, 179, and 192, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 157, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:178, 183, and 193, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 157, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:178, 183, and 194, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 6, and 376, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:30, 399, and 415, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:380, 400, and 416, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 10, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:33, 43, and 421, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 6, and 155, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:177, 182, and 191, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 372, and 376, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:381, 401, and 417, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 6, and 376, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:382, 402, and 418, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 6, and 377, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:383, 403, and 419, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:384, 39, and 54, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 10, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:385, 180, and 58, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 373, and 152, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:175, 180, and 188, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 6, and 11, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:386, 404, and 420, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 378, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:33, 43, and 421, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 9, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:387, 405, and 422, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 9, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:388, 406, and 423, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 9, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:388, 407, and 424, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 6, and 376, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:389, 408, and 425, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 157, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:390, 183, and 193, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 374, and 9, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:391, 409, and 426, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:392, 40, and 427, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:394, 39, and 429, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:395, 411, and 430, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:28, 39, and 49, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 10, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:396, 412, and 431, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 10, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:396, 412, and 58, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 10, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:397, 413, and 432, respectively; or the V_(H)region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:398, 414, and 433, respectively.
 3. The method ofclaim 1, wherein: the V_(H) region and the V_(L) region comprise aminoacid sequences having at least 90% sequence identity to SEQ ID NOS:110and 116, respectively; the V_(H) region and the V_(L) region compriseamino acid sequences having at least 90% sequence identity to SEQ IDNOS:111 and 117, respectively; the V_(H) region and the V_(L) regioncomprise amino acid sequences having at least 90% sequence identity toSEQ ID NOS:110 and 118, respectively; the V_(H) region and the V_(L)region comprise amino acid sequences having at least 90% sequenceidentity to SEQ ID NOS:110 and 119, respectively; the V_(H) region andthe V_(L) region comprise amino acid sequences having at least 90%sequence identity to SEQ ID NOS:110 and 120, respectively; the V_(H)region and the V_(L) region comprise amino acid sequences having atleast 90% sequence identity to SEQ ID NOS:110 and 121, respectively; theV_(H) region and the V_(L) region comprise amino acid sequences havingat least 90% sequence identity to SEQ ID NOS:110 and 122, respectively;the V_(H) region and the V_(L) region comprise amino acid sequenceshaving at least 90% sequence identity to SEQ ID NOS:110 and 123,respectively; the V_(H) region and the V_(L) region comprise amino acidsequences having at least 90% sequence identity to SEQ ID NOS:112 and124, respectively; the V_(H) region and the V_(L) region comprise aminoacid sequences having at least 90% sequence identity to SEQ ID NOS:113and 125, respectively; the V_(H) region and the V_(L) region compriseamino acid sequences having at least 90% sequence identity to SEQ IDNOS:114 and 126, respectively; the V_(H) region and the V_(L) regioncomprise amino acid sequences having at least 90% sequence identity toSEQ ID NOS:115 and 127, respectively; the V_(H) region and the V_(L)region comprise amino acid sequences having at least 90% sequenceidentity to SEQ ID NOS:247 and 257, respectively; the V_(H) region andthe V_(L) region comprise amino acid sequences having at least 90%sequence identity to SEQ ID NOS:248 and 258, respectively; the V_(H)region and the V_(L) region comprise amino acid sequences having atleast 90% sequence identity to SEQ ID NOS:249 and 259, respectively; theV_(H) region and the V_(L) region comprise amino acid sequences havingat least 90% sequence identity to SEQ ID NOS:250 and 260, respectively;the V_(H) region and the V_(L) region comprise amino acid sequenceshaving at least 90% sequence identity to SEQ ID NOS:251 and 261,respectively; the V_(H) region and the V_(L) region comprise amino acidsequences having at least 90% sequence identity to SEQ ID NOS:252 and262, respectively; the V_(H) region and the V_(L) region comprise aminoacid sequences having at least 90% sequence identity to SEQ ID NOS:253and 263, respectively; the V_(H) region and the V_(L) region compriseamino acid sequences having at least 90% sequence identity to SEQ IDNOS:254 and 264, respectively; the V_(H) region and the V_(L) regioncomprise amino acid sequences having at least 90% sequence identity toSEQ ID NOS:255 and 265, respectively; the V_(H) region and the V_(L)region comprise amino acid sequences having at least 90% sequenceidentity to SEQ ID NOS:256 and 266, respectively; the V_(H) region andthe V_(L) region comprise amino acid sequences having at least 90%sequence identity to SEQ ID NOS:256 and 267, respectively; the V_(H)region and the V_(L) region comprise amino acid sequences having atleast 90% sequence identity to SEQ ID NOS:518 and 534, respectively; theV_(H) region and the V_(L) region comprise amino acid sequences havingat least 90% sequence identity to SEQ ID NOS:519 and 535, respectively;the V_(H) region and the V_(L) region comprise amino acid sequenceshaving at least 90% sequence identity to SEQ ID NOS:115 and 536,respectively; the V_(H) region and the V_(L) region comprise amino acidsequences having at least 90% sequence identity to SEQ ID NOS:520 and264, respectively; the V_(H) region and the V_(L) region comprise aminoacid sequences having at least 90% sequence identity to SEQ ID NOS:521and 537, respectively; the V_(H) region and the V_(L) region compriseamino acid sequences having at least 90% sequence identity to SEQ IDNOS:522 and 538, respectively; the V_(H) region and the V_(L) regioncomprise amino acid sequences having at least 90% sequence identity toSEQ ID NOS:523 and 539, respectively; the V_(H) region and the V_(L)region comprise amino acid sequences having at least 90% sequenceidentity to SEQ ID NOS:519 and 540, respectively; the V_(H) region andthe V_(L) region comprise amino acid sequences having at least 90%sequence identity to SEQ ID NOS:524 and 541, respectively; the V_(H)region and the V_(L) region comprise amino acid sequences having atleast 90% sequence identity to SEQ ID NOS:525 and 261, respectively; theV_(H) region and the V_(L) region comprise amino acid sequences havingat least 90% sequence identity to SEQ ID NOS:526 and 542, respectively;the V_(H) region and the V_(L) region comprise amino acid sequenceshaving at least 90% sequence identity to SEQ ID NOS:527 and 543,respectively; the V_(H) region and the V_(L) region comprise amino acidsequences having at least 90% sequence identity to SEQ ID NOS:528 and544, respectively; the V_(H) region and the V_(L) region comprise aminoacid sequences having at least 90% sequence identity to SEQ ID NOS:529and 545, respectively; the V_(H) region and the V_(L) region compriseamino acid sequences having at least 90% sequence identity to SEQ IDNOS:528 and 546, respectively; the V_(H) region and the V_(L) regioncomprise amino acid sequences having at least 90% sequence identity toSEQ ID NOS:522 and 547, respectively; the V_(H) region and the V_(L)region comprise amino acid sequences having at least 90% sequenceidentity to SEQ ID NOS:256 and 548, respectively; the V_(H) region andthe V_(L) region comprise amino acid sequences having at least 90%sequence identity to SEQ ID NOS:530 and 549, respectively; the V_(H)region and the V_(L) region comprise amino acid sequences having atleast 90% sequence identity to SEQ ID NOS:531 and 550, respectively; theV_(H) region and the V_(L) region comprise amino acid sequences havingat least 90% sequence identity to SEQ ID NOS:519 and 552, respectively;the V_(H) region and the V_(L) region comprise amino acid sequenceshaving at least 90% sequence identity to SEQ ID NOS:110 and 553,respectively; the V_(H) region and the V_(L) region comprise amino acidsequences having at least 90% sequence identity to SEQ ID NOS:110 and118, respectively; the V_(H) region and the V_(L) region comprise aminoacid sequences having at least 90% sequence identity to SEQ ID NOS:533and 554, respectively; the V_(H) region and the V_(L) region compriseamino acid sequences having at least 90% sequence identity to SEQ IDNOS:115 and 555, respectively; the V_(H) region and the V_(L) regioncomprise amino acid sequences having at least 90% sequence identity toSEQ ID NOS:524 and 556, respectively; or the V_(H) region and the V_(L)region comprise amino acid sequences having at least 90% sequenceidentity to SEQ ID NOS:519 and 557, respectively.
 4. The method of claim1, wherein: the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:110 and 116, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:111 and 117, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:110 and 118, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:110 and 119, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:110 and 120,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:110 and 121, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:110 and 122, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:110 and 123, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:112 and 124, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:113 and 125,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:114 and 126, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:115 and 127, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:247 and 257, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:248 and 258, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:249 and 259,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:250 and 260, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:251 and 261, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:252 and 262, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:253 and 263, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:254 and 264,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:255 and 265, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:256 and 266, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:256 and 267, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:518 and 534, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:519 and 535,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:115 and 536, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:520 and 264, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:521 and 537, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:522 and 538, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:523 and 539,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:519 and 540, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:524 and 541, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:525 and 261, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:526 and 542, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:527 and 543,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:528 and 544, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:529 and 545, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:528 and 546, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:522 and 547, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:256 and 548,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:530 and 549, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:531 and 550, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:519 and 552, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:110 and 553, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:110 and 118,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:533 and 554, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:115 and 555, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:524 and 556, respectively;or the V_(H) and V_(L) regions comprise the amino acid sequences setforth in SEQ ID NOS:519 and 557, respectively.
 5. The method of claim 1,wherein the anti-BCMA antibody or antigen-binding fragment thereof is anscFv.
 6. The method of claim 5, wherein the V_(H) region isamino-terminal to the V_(L) region or the V_(H) region iscarboxy-terminal to the V_(L) region.
 7. The method of claim 5, whereinthe scFv comprises an amino acid sequence selected from any one of SEQID NOS:128-139, 268-278, 558-576 and 578-583, or an amino acid sequencehaving at least 90% sequence identity to an amino acid sequence selectedfrom any one of SEQ ID NOS:128-139, 268-278, 558-576 and 578-583.
 8. Themethod of claim 1, wherein the antibody or antigen-binding fragmentthereof is human.
 9. The method of claim 1, wherein the intracellularsignaling domain comprises a primary signaling domain, a signalingdomain that is capable of inducing a primary activation signal in a Tcell, a signaling domain of a T cell receptor (TCR) component, and/or asignaling domain comprising an immunoreceptor tyrosine-based activationmotif (ITAM).
 10. The method of claim 1, wherein the intracellularsignaling domain comprises an intracellular signaling domain of aCD3-zeta (CD3) chain.
 11. The method of claim 1, wherein theintracellular signaling region further comprises a costimulatorysignaling domain.
 12. The method of claim 11, wherein the costimulatorysignaling domain comprises an intracellular signaling domain of a CD28,a 4-1BB or an ICOS.
 13. The method of claim 1, wherein the disease ordisorder is a cancer.
 14. The method of claim 1, wherein the disease ordisorder is multiple myeloma.
 15. A method of treatment, the methodcomprising administering to a subject having a disease or disorderassociated with BCMA an anti-BCMA antibody or antigen-binding fragment,wherein the anti-BCMA antibody or antigen-binding fragment comprises aheavy chain variable (V_(H)) region and a light chain variable (V_(L))region, wherein: the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:110,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:116; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:111, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:117; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:110, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:118; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:110,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:119; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:110, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:120; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:110, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:121; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:110,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:122; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:110, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:123; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:112, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:124; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:113,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:125; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:114, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:126; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:115, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:127; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:247,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:257; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:248, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:258; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:249, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:259; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:250,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:260; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:251, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:261; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:252, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:262; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:253,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:263; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:254, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:264; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:255, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:265; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:256,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:266; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:256, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:267; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:518, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:534; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:519,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:535; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:115, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:536; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:520, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:264; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:521,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:537; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:522, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:538; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:523, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:539; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:519,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:540; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:524, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:541; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:525, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:261; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:526,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:542; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:527, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:543; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:528, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:544; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:529,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:545; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:528, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:546; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:522, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:547; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:256,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:548; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:530, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:549; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:531, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:550; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:519,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:552; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:110, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:553; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:110, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:118; the V_(H) region comprises a CDR-H1, CDR-H2 and CDR-H3contained within the V_(H) region amino acid sequence of SEQ ID NO:533,and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3 containedwithin the V_(L) region amino acid sequence of SEQ ID NO:554; the V_(H)region comprises a CDR-H1, CDR-H2 and CDR-H3 contained within the V_(H)region amino acid sequence of SEQ ID NO:115, and the V_(L) regioncomprises a CDR-L1, CDR-L2 and CDR-L3 contained within the V_(L) regionamino acid sequence of SEQ ID NO:555; the V_(H) region comprises aCDR-H1, CDR-H2 and CDR-H3 contained within the V_(H) region amino acidsequence of SEQ ID NO:524, and the V_(L) region comprises a CDR-L1,CDR-L2 and CDR-L3 contained within the V_(L) region amino acid sequenceof SEQ ID NO:556; or the V_(H) region comprises a CDR-H1, CDR-H2 andCDR-H3 contained within the V_(H) region amino acid sequence of SEQ IDNO:519, and the V_(L) region comprises a CDR-L1, CDR-L2 and CDR-L3contained within the V_(L) region amino acid sequence of SEQ ID NO:557,respectively.
 16. The method of claim 15, wherein: the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:26, 37, and 47, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 8, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:27, 38, and 48, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:28, 39, and 49, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:29, 40, and 50, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:30, 39, and 51, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:31, 41, and 52, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:32, 42, and 53, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:30, 39, and 54, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 9, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:33, 43, and 55, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 10, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:34, 44, and 56, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 6, and 11, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:35, 45, and 57, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 10, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:36, 46, and 58, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:140, 145, and 149, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:174, 179, and 184, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:141, 145, and 149, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:174, 179, and 185, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:141, 145, and 150, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:174, 179, and 186, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:142, 146, and 151, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:174, 179, and 187, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 152, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:175, 180, and 188, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:143, 147, and 153, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:174, 179, and 189, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:144, 148, and 154, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:176, 181, and 190, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 6, and 155, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:177, 182, and 191, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 156, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:174, 179, and 192, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 157, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:178, 183, and 193, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 157, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:178, 183, and 194, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 6, and 376, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:30, 399, and 415, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:380, 400, and 416, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 10, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:33, 43, and 421, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 6, and 155, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:177, 182, and 191, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 372, and 376, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:381, 401, and 417, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 6, and 376, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:382, 402, and 418, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 6, and 377, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:383, 403, and 419, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:384, 39, and 54, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 10, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:385, 180, and 58, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 373, and 152, respectively, and the V_(L)region comprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:175, 180, and 188, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 6, and 11, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:386, 404, and 420, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 378, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:33, 43, and 421, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 9, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:387, 405, and 422, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 9, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:388, 406, and 423, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 9, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:388, 407, and 424, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:3, 6, and 376, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:389, 408, and 425, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 157, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:390, 183, and 193, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 374, and 9, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:391, 409, and 426, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:392, 40, and 427, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:394, 39, and 429, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:395, 411, and 430, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:28, 39, and 49, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 10, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:396, 412, and 431, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 10, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:396, 412, and 58, respectively; the V_(H) regioncomprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:2, 5, and 10, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:397, 413, and 432, respectively; or the V_(H)region comprises a CDR-H1, CDR-H2, and CDR-H3 comprising the amino acidsequence of SEQ ID NOS:1, 4, and 7, respectively, and the V_(L) regioncomprises a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acidsequence of SEQ ID NOS:398, 414, and 433, respectively.
 17. The methodof claim 15, wherein: the V_(H) region and the V_(L) region compriseamino acid sequences having at least 90% sequence identity to SEQ IDNOS:110 and 116, respectively; the V_(H) region and the V_(L) regioncomprise amino acid sequences having at least 90% sequence identity toSEQ ID NOS:111 and 117, respectively; the V_(H) region and the V_(L)region comprise amino acid sequences having at least 90% sequenceidentity to SEQ ID NOS:110 and 118, respectively; the V_(H) region andthe V_(L) region comprise amino acid sequences having at least 90%sequence identity to SEQ ID NOS:110 and 119, respectively; the V_(H)region and the V_(L) region comprise amino acid sequences having atleast 90% sequence identity to SEQ ID NOS:110 and 120, respectively; theV_(H) region and the V_(L) region comprise amino acid sequences havingat least 90% sequence identity to SEQ ID NOS:110 and 121, respectively;the V_(H) region and the V_(L) region comprise amino acid sequenceshaving at least 90% sequence identity to SEQ ID NOS:110 and 122,respectively; the V_(H) region and the V_(L) region comprise amino acidsequences having at least 90% sequence identity to SEQ ID NOS:110 and123, respectively; the V_(H) region and the V_(L) region comprise aminoacid sequences having at least 90% sequence identity to SEQ ID NOS:112and 124, respectively; the V_(H) region and the V_(L) region compriseamino acid sequences having at least 90% sequence identity to SEQ IDNOS:113 and 125, respectively; the V_(H) region and the V_(L) regioncomprise amino acid sequences having at least 90% sequence identity toSEQ ID NOS:114 and 126, respectively; the V_(H) region and the V_(L)region comprise amino acid sequences having at least 90% sequenceidentity to SEQ ID NOS:115 and 127, respectively; the V_(H) region andthe V_(L) region comprise amino acid sequences having at least 90%sequence identity to SEQ ID NOS:247 and 257, respectively; the V_(H)region and the V_(L) region comprise amino acid sequences having atleast 90% sequence identity to SEQ ID NOS:248 and 258, respectively; theV_(H) region and the V_(L) region comprise amino acid sequences havingat least 90% sequence identity to SEQ ID NOS:249 and 259, respectively;the V_(H) region and the V_(L) region comprise amino acid sequenceshaving at least 90% sequence identity to SEQ ID NOS:250 and 260,respectively; the V_(H) region and the V_(L) region comprise amino acidsequences having at least 90% sequence identity to SEQ ID NOS:251 and261, respectively; the V_(H) region and the V_(L) region comprise aminoacid sequences having at least 90% sequence identity to SEQ ID NOS:252and 262, respectively; the V_(H) region and the V_(L) region compriseamino acid sequences having at least 90% sequence identity to SEQ IDNOS:253 and 263, respectively; the V_(H) region and the V_(L) regioncomprise amino acid sequences having at least 90% sequence identity toSEQ ID NOS:254 and 264, respectively; the V_(H) region and the V_(L)region comprise amino acid sequences having at least 90% sequenceidentity to SEQ ID NOS:255 and 265, respectively; the V_(H) region andthe V_(L) region comprise amino acid sequences having at least 90%sequence identity to SEQ ID NOS:256 and 266, respectively; the V_(H)region and the V_(L) region comprise amino acid sequences having atleast 90% sequence identity to SEQ ID NOS:256 and 267, respectively; theV_(H) region and the V_(L) region comprise amino acid sequences havingat least 90% sequence identity to SEQ ID NOS:518 and 534, respectively;the V_(H) region and the V_(L) region comprise amino acid sequenceshaving at least 90% sequence identity to SEQ ID NOS:519 and 535,respectively; the V_(H) region and the V_(L) region comprise amino acidsequences having at least 90% sequence identity to SEQ ID NOS:115 and536, respectively; the V_(H) region and the V_(L) region comprise aminoacid sequences having at least 90% sequence identity to SEQ ID NOS:520and 264, respectively; the V_(H) region and the V_(L) region compriseamino acid sequences having at least 90% sequence identity to SEQ IDNOS:521 and 537, respectively; the V_(H) region and the V_(L) regioncomprise amino acid sequences having at least 90% sequence identity toSEQ ID NOS:522 and 538, respectively; the V_(H) region and the V_(L)region comprise amino acid sequences having at least 90% sequenceidentity to SEQ ID NOS:523 and 539, respectively; the V_(H) region andthe V_(L) region comprise amino acid sequences having at least 90%sequence identity to SEQ ID NOS:519 and 540, respectively; the V_(H)region and the V_(L) region comprise amino acid sequences having atleast 90% sequence identity to SEQ ID NOS:524 and 541, respectively; theV_(H) region and the V_(L) region comprise amino acid sequences havingat least 90% sequence identity to SEQ ID NOS:525 and 261, respectively;the V_(H) region and the V_(L) region comprise amino acid sequenceshaving at least 90% sequence identity to SEQ ID NOS:526 and 542,respectively; the V_(H) region and the V_(L) region comprise amino acidsequences having at least 90% sequence identity to SEQ ID NOS:527 and543, respectively; the V_(H) region and the V_(L) region comprise aminoacid sequences having at least 90% sequence identity to SEQ ID NOS:528and 544, respectively; the V_(H) region and the V_(L) region compriseamino acid sequences having at least 90% sequence identity to SEQ IDNOS:529 and 545, respectively; the V_(H) region and the V_(L) regioncomprise amino acid sequences having at least 90% sequence identity toSEQ ID NOS:528 and 546, respectively; the V_(H) region and the V_(L)region comprise amino acid sequences having at least 90% sequenceidentity to SEQ ID NOS:522 and 547, respectively; the V_(H) region andthe V_(L) region comprise amino acid sequences having at least 90%sequence identity to SEQ ID NOS:256 and 548, respectively; the V_(H)region and the V_(L) region comprise amino acid sequences having atleast 90% sequence identity to SEQ ID NOS:530 and 549, respectively; theV_(H) region and the V_(L) region comprise amino acid sequences havingat least 90% sequence identity to SEQ ID NOS:531 and 550, respectively;the V_(H) region and the V_(L) region comprise amino acid sequenceshaving at least 90% sequence identity to SEQ ID NOS:519 and 552,respectively; the V_(H) region and the V_(L) region comprise amino acidsequences having at least 90% sequence identity to SEQ ID NOS:110 and553, respectively; the V_(H) region and the V_(L) region comprise aminoacid sequences having at least 90% sequence identity to SEQ ID NOS:110and 118, respectively; the V_(H) region and the V_(L) region compriseamino acid sequences having at least 90% sequence identity to SEQ IDNOS:533 and 554, respectively; the V_(H) region and the V_(L) regioncomprise amino acid sequences having at least 90% sequence identity toSEQ ID NOS:115 and 555, respectively; the V_(H) region and the V_(L)region comprise amino acid sequences having at least 90% sequenceidentity to SEQ ID NOS:524 and 556, respectively; or the V_(H) regionand the V_(L) region comprise amino acid sequences having at least 90%sequence identity to SEQ ID NOS:519 and 557, respectively.
 18. Themethod of claim 15, wherein: the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:110 and 116, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:111 and 117, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:110 and 118,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:110 and 119, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:110 and 120, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:110 and 121, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:110 and 122, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:110 and 123,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:112 and 124, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:113 and 125, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:114 and 126, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:115 and 127, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:247 and 257,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:248 and 258, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:249 and 259, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:250 and 260, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:251 and 261, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:252 and 262,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:253 and 263, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:254 and 264, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:255 and 265, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:256 and 266, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:256 and 267,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:518 and 534, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:519 and 535, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:115 and 536, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:520 and 264, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:521 and 537,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:522 and 538, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:523 and 539, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:519 and 540, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:524 and 541, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:525 and 261,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:526 and 542, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:527 and 543, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:528 and 544, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:529 and 545, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:528 and 546,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:522 and 547, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:256 and 548, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:530 and 549, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:531 and 550, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:519 and 552,respectively; the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:110 and 553, respectively; the V_(H)and V_(L) regions comprise the amino acid sequences set forth in SEQ IDNOS:110 and 118, respectively; the V_(H) and V_(L) regions comprise theamino acid sequences set forth in SEQ ID NOS:533 and 554, respectively;the V_(H) and V_(L) regions comprise the amino acid sequences set forthin SEQ ID NOS:115 and 555, respectively; the V_(H) and V_(L) regionscomprise the amino acid sequences set forth in SEQ ID NOS:524 and 556,respectively; or the V_(H) and V_(L) regions comprise the amino acidsequences set forth in SEQ ID NOS:519 and 557, respectively.
 19. Themethod of claim 15, wherein the disease or disorder is a cancer.
 20. Themethod of claim 15, wherein the disease or disorder is multiple myeloma.